All about Gilbert's syndrome. Hereditary hyperbilirubinemia. Gilbert's syndrome See what "heterozygote" is in other dictionaries

A mutation in the MTHFR gene is one of the most common thrombophilic mutations, the presence of which can be accompanied by an increase in the level of homocysteine in the blood and an increased risk of complications of atherosclerosis, thrombosis, and pathology of pregnancy.

What is MTHFR?

MTHFR or MTHFR is an enzyme - methylenetetrahydrofolate reductase, key in the conversion of amino acids. Mutation in the MTHFR gene is the most studied cause of congenital thrombophilia.

Folic acid, passing through several biochemical transformations, through the enzyme methylenetetrahydrofolate reductase - MTHFR turns into methionine synthase (MTR). Methionine synthesis, in turn, converts homocysteine to methionine.

Folate or vitamin B9 is used in many biological processes:

homocysteine methylation – i.e. its neutralization
synthesis of components for DNA and RNA
synthesis of nerve impulse transmitters, proteins and phospholipids

A change in the MTHFR gene leads to an increase in the level of homocysteine in the blood - hyperhomocysteinemia, which can also be provoked by a deficiency of B vitamins in food (B6, B12, folic acid - B9). Homocysteine has a high chemical activity, which, when accumulated, can turn into aggressiveness and toxicity.

Homocysteine is a non-essential amino acid that the body can synthesize on its own from the essential amino acid methionine.

The enzyme 5,10-methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the main form of folate in the body. Folates are donors of monocarbonates in many metabolic reactions, including homocysteine methylation.

Point mutations (mutation = error) in the MTHFR gene lead to the appearance of an enzyme with increased thermolability and reduced activity, which is manifested by an increase in the level of homocysteine in the blood. Homocysteine has a cytotoxic effect on the cells of the inner lining of blood vessels (endothelium), inhibits their division, stimulates the thickening of the muscle layer of the vascular wall, stimulates the formation of blood clots, which gives rise to the development and progression of atheroslerosis with its complications and increases the risk of thrombosis by 3 times.

Homocysteine on the endothelium inhibits the expression of thrombomodulin and thus the activation of protein C. Accompanied by an increase in activityVandXII(5 and 12) blood clotting factors.

A positive result of the MTHFR gene mutation must be supplemented by a study of the level of homocysteine in the blood.

A positive MTHFR mutation without an increase in homocysteine has no clinical significance.

The mutation in the MTHFR gene does not have any symptoms; it cannot be detected without a special PCR analysis.

How to warn?

You can "decapitate" the MTHFR mutation in the first place with proper nutrition. Especially during pregnancy, you need to provide yourself and the developing fetus with an adequate supply of vitamins.

In second place is the intake of folic acid preparations and B vitamins.

Food sources of folic acid:

leafy vegetables - all types of salads

vegetables - cauliflower, broccoli, white cabbage, cauliflower, tomatoes, radishes, melons, cucumbers, beans, peascereals - all coarse grains, cereals, sprouted grains

fruits - mangoes, oranges, bananas, avocados, cherries, cherries, strawberries, raspberries, agrus

nuts - walnuts, pistachios

some dairy products - soft and moldy cheeses

meat - the largest amount is found in the liver

Types of mutations in the MTHFR gene

More than 25 types of MTHFR mutations have been described, but only two are important in the practical work of a doctor, in which MTHFR activity is reduced:

A1298C - replacement of adenine (A) with cytosine (C) at nucleotide 1298
C677T - cytosine (C) is replaced by thymine (T) at position 677, which leads to a change in the synthesized amino acid from alanine to valine at position 223 of the protein chain

Mutation MTHFR C677T is a risk factor for splitting of the neural tube (back bifida) and the anterior abdominal wall (hernia of the umbilical cord, gastroschisis, omphalocele). With a homozygous variant of the MTHFR mutation in the mother, the risk of such a complication in the fetus is 2 times higher. Simultaneous deficiency of folic acid and folate increases the risk by 5 times.

Carrier options

heterozygotes - one gene is mutated, the second is "healthy"
homozygous - both genes are mutated
combined heterozygotes - two different genes encoding the synthesis of MTHFR are mutated

The frequency of heterozygous mutation of the MTHFR gene among the population of Europe, North America and Australia is 31-39%, homozygous - 9-17%. 15% combined heterozygotes with one mutation of the MTHFR gene C677T and A1298C.

The presence of three or more mutations in the MTHFR gene is not compatible with life.

Diseases associated with elevated homocysteine and MTHFR mutation

diseases of the heart and blood vessels - ischemic heart disease, cerebral atherosclerosis, myocardial infarction, stroke, endarteritis of the vessels of the legs
peptic ulcer of the stomach and 12 duodenal ulcer
inflammatory bowel disease - ulcerative colitis and Crohn's disease
Alzheimer's disease
multiple sclerosis
depression
migraine
chronic fatigue syndrome

Obstetric and gynecological consequences

Spontaneous abortions in the first trimester with an MTHFR mutation are associated with a violation of implantation (attachment of a fertilized egg to the uterus), in the second and third trimesters - with blockage of placental vessels by blood clots.

infertility
unauthorized premature termination of pregnancy
preeclampsia
premature birth
premature detachment of the placenta
congenital malformations of the fetus
low birth weight

All the complications described above can be prevented by taking preparations containing the active form of folic acid, vitamin B12 and vitamin B6 (pyridoxine).

Dietary folic acid and vitamin B6 deficiencies worsen with increased fat intake because B vitamins are water soluble and not fat soluble. All this leads to insufficient absorption in the intestine.

How is it inherited?

The mode of inheritance of the MTHFR gene is autosomal dominant and does not depend on gender. Each cell contains two copies of this gene, inherited from the father and mother. The risk of having a child with this mutation is 25%. In order for the disease to manifest itself, both genes must be mutated (from the mother and from the father).

Indications

thrombosis of the veins of the lower extremities, stroke or transient cerebrovascular accident (mini-stroke) at a young age
a direct blood relative has a thrombophilic mutation (mother, father, sister, brother, son or daughter)
thrombosis in a direct blood relative at a young age up to 50 children
thrombosis of a vein of unusual localization (sinuses of the brain or liver)
recurrent thrombosis of any location
thrombosis while taking hormonal contraceptives or hormone replacement therapy with sex hormones (in menopause)
thrombosis during pregnancy, childbirth, postpartum period
infertility, unsuccessful IVF attempts (IVF)
complicated pregnancy (current or previous)
planned major surgery with a high risk of thrombosis
taking antiepileptic drugs and drugs that disrupt the metabolism of folic acid

MTHFR gene mutation A1298C and C677T was last modified: October 8th, 2017 by Maria Bodyan

More and more attention of doctors in private practice here (in the USA) is captured by important and already quite well studied genetic polymorphisms. In this regard, I decided to post on the blog the interpretation of genetic analysis for a girl, one of my dear clients. In our practice here, perhaps, in every second case, and especially in case of “failures” with conception / bearing, with autism, developmental delay, depression, panic attacks, chronic fatigue syndrome, CVD, high homocysteine, etc. (read below), we work with a genetic laboratory, only much wider than what we were able to consider with Ekaterina.

In a specific case, we tested for such gene variations (see below) in the biochemical pathway (SUPER IMPORTANT for the optimal functioning of our body) - METHYLATION.

It must be said that DNA methylation is the most studied epigenetic modification for the last decade. If I just said something in “foreign” for someone, then I’m talking about the mechanisms for controlling gene activity in the process of development / formation of the body, about internal factors that will affect the development of the body with the exception of the very factor of change in the DNA sequence - the primary (original) structure of DNA.

Tests have been carried out on:

MTHFR C677T
MTHFR A1298C
MTR 2756
MTRR 66

3 genes and their variations, the work of which is based on two IMPORTANT components of our biochemistry: vit B12, folate.

Good afternoon, Katya!)

To start,

Homozygous - both genes are changed (we get a gene from each parent).

Heterozygous - one of the genes is changed.

The numbers next to the name of the genes indicate alleles - two different forms of the same gene. Different alleles can give variations in the characteristics encoded by a given gene.

Genes code for important proteins (enzymes) that trigger a particular step in a particular biochemical pathway.

Dysfunctions or functions of genes as a result of their variations (mutations) are not absolute, they are markers of potential problems under the influence of certain conditions of our environment, for example, accumulation and intoxication with mercury, especially tiromesal significantly compromises MTR - methionine synthase enzyme (read below).

According to your analysis for the above gene variations:

Three heterozygotes in the cycles of the biochemical pathway Methylation: MTHFR (S677T), MTR, MTRR. I will note that this is a large biochemical pathway, not only the enzymes encoded by these genes that we tested are involved in it, or rather, you will find that several biochemical pathways are intertwined (woven) with Methylation.

These 3 heterozygotes are also at the junction and affect the BH4 (tetrahydrabiopterin) part/cycle of methylation, and it in turn affects them. Although it should be noted that, according to all the scientific articles that have taken place so far, the A1298C mutation has a greater effect on the tetrahydrobiopterin cycle.

Scheme of the biochemical cycle - Methylation, if you look at one eye for the most curious:

Impressive, huh?

It is also easy to get acquainted with the genes that we considered in your analyzes:

- You have one heterozygous in the folate methylation cycle, in the 677-part of the MTHFR gene (encoding the enzyme methyl-tetrahydrofolate reductase) and variations in this part of the gene are more significant than in the A1298 part and ESPECIALLY if they were combined with variations in A1298, or would be in a homozygous state , you have a heterozygote that is a milder mutation.

And 2 heterozygotes in terms of transformation homocysteine to methionine in the same biochiochemical pathway - methylation, where B12 plays a key role, all together such heterozygotes enhance - exacerbate - aggravate, sum up in the effect.

Heterozygous - MTHFR C677T in this case reduces by 30-40% the efficiency and rate of conversion of folate to its active form 5-methyltetrahydrofolate, which is necessary for B12 methylation in order to convert homocysteine to methionine and then to SAMe (the main donor of CH3 groups).

Heterozygous in the MTR 2756 gene, this is a gene that encodes methyl synthase, an enzyme that is necessary to convert homocysteine to methionine and is B12 dependent, and needs already methylated B12 i e METHYLcobalamin (the active form of vit B12); mutations in this case increase function and deplete CH3-methylation groups. Variability MTRR66 (methyl synthase reductase) - regenerates methyl-B12 for MRR, thus will exacerbate MTR performance. Fortunately, heterozygote MTRR A66G is a fairly mild mutation when compared to the MTRR11 variant (which we have not tested).

So what is possible in this scenario? Increasing the level of homocysteine, which is a rather serious risk of thrombosis, CVD, strokes, heart attacks, high homocysteine also has a neurotoxic effect. See below for additional risks.

Polymorphism of the MTRR gene is associated with Down syndrome, acute leukemia, pancreatic cancer, Crohn's, ulcerative colitis, congenital heart defects.

You understand that we are talking, firstly, about associations, and secondly, we are not talking about a “sentence”, but about the possible consequences of an individually low level of vit B12. By themselves, SNPs polymorphisms do not cause diseases, nutrient deficiencies under the onslaught of slippage due to gene “blocks” and lifestyle (nutrition, intoxication, etc.) cause them, or so far only symptoms, even without diagnoses.
Remember, you have repeatedly asked the question that you have “just the opposite” high vit B12 in the blood (I observe this in a fairly high percentage of my clients), I have already answered you personally, but these results support the scenario when vit B12 is in the blood B12 in an inactive form cannot effectively access tissues (intracellularly) and be converted into biochemically active B12-methylcobalamin.

Lithium helps transport B12 and folate into cells. In this case, I am not talking about pharmacological lithium, which is widely used in psychiatry.

It must be said that in cases of heterozygotes, the estimated retained function is 60-70%, if only one or two gene polymorphisms are considered, without taking into account the influence of other polymorphisms on one or another biochemical pathway.

Regarding the BH4 cycle, in general, there is a close relationship between folate and biopterin metabolism, in particular, the participation of dihydrobiopterin reductase (such an enzyme in the BH4 cycle) in the metabolism of tetrahydrofolic acid:
The BH4 cycle is important for:

For further conversion of phenylalanine into tyrosine, and from it both thyroid and adrenal hormones are already formed, and the neurotransmitter - dopamine, adrenaline, norepinephrine.
Formation of (repeat) neurotransmitters:

Serotonin (“peace in the soul and mind”, “good mood” neurotransmitter, melatonin (sleep neurotransmitter), dopamine (motivation, control over the situation, satisfaction), adrenaline / norepinephrine (takeoff, rise - we also need these, but for a short time , not permanently chronically elevated).

cofactor in the formation of nitric oxide (natural nitroglycerin - vasodilation, erection, etc.)

To summarize, with such heterozygotes, we can mean, especially if part of the A1298C gene was also involved, which is possible, that is, there is an increased risk of: psycho / emotional disorders (like bipolar disorder, depression, etc.), migraines, insomnia, carcinogenic diseases, obesity, peripheral arterial disease, vascular problems of the placenta (missed pregnancy), congenital malformations of the fetus, deep vein thrombosis, Alzheimer's and other cognitive impairments, Parkinson's disease, erectile dysfunction, increased risk of thrombosis / CVD / cerebrovascular disorders, early strokes (before 45 years), inflammatory bowel disease (Crohn, ulcerative colitis), Irritable Bowel Syndrome.

Migraine with aura (bright/specific odors or visual-light flashes, etc.) are especially associated with C677T mutations. Mutations of this type also predispose to anxiety and mood fluctuations, which again explains why for some, severe stress does not cause a “breakdown” of neurotransmitters, while for others it results in a disease. In order for such a CLEARLY to take place, one heterozygote is still not enough, we are again talking about “associations”, a number of polymorphisms reinforcing others, and the multifactorial nature of the disease as a whole. For whom it is not clear, once again, that is, if you do not have symptoms, for example, panic attacks, then with certain heterozygotes in the methylation pathway and in the course of a lifestyle associated with high levels of stress, including eating style, you are much more prone to panic attacks. attacks, CVD, recurrent miscarriage than a group of people who do not have such heterozygous genetic variations of these genes that tell us that you need much higher doses of active forms of vit B12 and folic acid in order for the risks not to take place, not to show myself.

In your case, Katya, it would be nice to see additionally: COMT, CBS and BHMT - gene polymorphisms.

The biochemical pathway of methylation is a very delicate process to interpret, if for example there is a homozygous (+ \ +) for COMT, then you will better tolerate the form of vit B12 - hydroxycobalamin, rather than methylcobalamin and gradually replacing it with methylcobalamin. It is impossible to consider in detail ALL of these gene polymorphisms in one blog, but they are all interconnected with each other. ", cause irritability along with a feeling of depression or other symptoms of" not in horse food ".

Polymorphisms in methylation genes have been highly associated, based on recent studies, with the autism spectrum. Having information about such associations and test results initially (as early as possible, I think it would be great to check such genetic variations from childhood), then individual symptoms are already taken into account and additional research methods are considered, such as AND, MOST IMPORTANTLY, this is super important As I always teach my clients, before doing any test, ask the experts and yourself what practical approach it gives, what can be changed after you have read the results, the main thing is to develop practical approaches / actions for prevention or effective treatment. We should never do a biopsy and CT just because “what if” or “interesting”, or just to establish the fact, we need to start from “what will this change in my actions / approaches”. Or a more successful example, which gives in terms of approaches the definition of allergens according to the Ig E panel, NOTHING, except for “all my life” (seriously ???) to avoid encountering these allergens (animal hair, pollen such and such, strawberries, etc. It is still necessary to contrive to avoid everything that possibly can show Ig E). Do you understand what I mean? This is not the cause, these results are the CONSEQUENCE. Consequences only "treat" pharmaceuticals and operations, or rather they mask them. “Here, I have lost sensitivity in my foot, how great, you can now dance on the stove!” - Approximately so.

Homozygous C677T increases the risk of death from CVD by three times, based on studies.

A significant level of association occurs between folate gene variations and schizophrenia. For all the risks I have listed above, there are scientific studies that support such correlations, as well as a number of diseases, symptoms, which have a positive effect on taking "high doses" (individually "high") folate/B12.

Here's a good, or rather, it's scary, movie to watch about a deficiency of vit B12. The story of a doctor who was practically on the verge of death, who was mistakenly diagnosed with leukemia and was already offered hospice services (a hospital for the doomed), is this not a paradox?

vitamin deficiencyB12 can cause severe fatigue (before the diagnosis of Chronic Fatigue Syndrome), severe weakness (until it is impossible to hold a hair dryer or even a pen in your hands), feeling short of breath, constipation, loss of appetite, panic attacks, depression. It can also be observed: a violation of the sense of balance, confusion, dementia, memory impairment, stomatitis. Vitamin B12 deficiency often in certain individuals will give out the symptoms of multiple sclerosis syndrome due to its effect on the musculoskeletal system and especially the nerve fibers of the spinal cord.

Ekaterina, did you manage to catch from the text that the status of vit B12 in the blood can be high, and high methylmalanic acid in the urine will indicate an intracellular B12 deficiency?

In order to accurately determine the individual deficiency of vitamin B12, the following tests are done:

The level of vit B12 in the blood

Methylmalanic acid in urine (vit B12 metabolite) - mandatory analysis

You can see, but it is difficult to find such an analysis - ur vit B12 in leukocytes

Homocysteine and a clinical blood test and specifically in it MCV

Genetic analyzes that we review in this blog

And finally, the symptoms, which may not yet be pronounced.

What should you do, Katya?

Ekaterina, you do not want supplements with folic acid (a form of supplementation common in Russia and the CIS countries for pregnant women) - the problem is that you cannot effectively transform it into an active form, but this recommendation is not as strict as if would be homozygous at 677 or an additional heterozygote at A1298.

It should be noted that in many flour foods, including bread and pasta, good food industries add this synthetic form of filic acid. In people with B12 deficiency, who use such products or folic acid in supplementation, B12 dependent anemia is masked, often hidden anemia - megaloblastic anemia, which is serious in its consequences, it is not visible on blood tests, while serious neuropathies are already formed against the background of intracellular vit B12 deficiency. As you understand, in this case, one-sided supplementation with folic acid is a double-edged sword. Unlike folic acid deficiency, vitamin B12 deficiency can result in subacute combined degeneration of the spinal cord, a serious problem.

Only with a severe B12 deficiency, a blood serum test will show a low level of vit B12. Do not forget that folates and methylcobalamin (the active form of vit B12) play their role intracellularly, and not in blood plasma and serum, so folates also look intracellularly (in leukocytes, in erythrocytes), or / and B12 and folate metabolites in URINE, which are more accurate and more sensitive assays. In the blood, their level should be at least at the average border of the lab norms, the level of vit B12 below 350 pg / ml is considered as a deficiency (despite any lab norms, this level is NOT OPTIMAL already for health and especially if supported by symptoms).

An elevated level of vit B12 in the blood should be alarming, as is an intracellular deficiency of vit B12.

Be aware of drugs that block the folate cycle, such as oral contraceptives, methotrexate, etc., or drugs that can increase homocysteine, especially when the side effects of drugs are not taken into account and are not compensated by nutrients, the reproduction / conversion / absorption of which they blocked, for example, antacids , drugs of the biguanide classes (like metformin), which block the absorption of vit B12, many ABs, drugs for chemotherapy. And if the person who takes them or/and is initially physically fit does not take into account such side effects of the drug, plus the individual specificity of the polymorphisms of the genes under consideration is superimposed, then the patient is aimed at getting a significant number of other health problems in the process of “treatment”. And so, as I have said more than once, "the patient becomes even more sick."
- Homocysteine, it should be noted, not all laboratories will measure as expected, therefore, it’s a good idea to check in a couple of different labs if there is a potential genetic risk or find out the details of the analysis from the laboratory doctors of your chosen laboratory. In general, blood is taken from a vein, not from a finger, early in the morning on an empty stomach and a day or two before the analysis you avoid foods rich in methionine (although I do not think that eating with methionine affects the level of homocysteine, if it is elevated, then elevated).

Periodically donate homocysteine, make sure that it is not at a high gr of the norm, in the middle or at a lower gr of the norm. When very low, this is also a problem, but this is a different path - the biochemical path of glutathione.

Constant intake of vitamin / min complexes with the vitamin B group, which are in rational proportions to each other, in ACTIVE forms, if we talk about folate, then these are tetrahydrofolates, which are then able to accept a carbon atom as a result of various catabolic reactions in the process of amino acid metabolism . Tetrahydrofolate serves as a carbon transporter and many, many, many reactions in the body depend on this step.
In your case, 800-1600 micrograms of 5-methyltetrahydrofolate per day (the active form of folic acid), 1000-3000 micrograms of sublingual methylcobalamin, low-dose lithium orotate courses are sufficient.

Do not forget that even sublingually, the absorption of vit B12 is somewhere around 20-30% of the dose. That is why, depending on the symptoms, but more often they use it s / c injections.

Additional cofactors involved in the folate/B12 cycle and biopterin BH4:

B6 (R-5-R) - you can drink courses,

We have not tested polymorphisms in your BH4 cycle, but the information is for you personally - infrared saunas promote detoxification and increase BH4. If there are variations there, then they would most likely consider supplementing them.
In MorNatural:

– Multi Thera 1 plus Vit K – ProThera 180 vcaps – vit/min complex with good doses of Vit B12 and folate – 6 capsules per day with meals in the morning.

- Vitamin B12 - Active B12 Folate - ProThera 1,000 mcg/800 mcg 60 tabs (B12 and folate to dissolve sublingually) - for you 1 X 1-2 times a day.

– Lithium Orotate – Complementary Prescriptions 130 mg 120 caps

– Multi Mineral Complex – Klaire Labs 100 vcaps – mineral complex (see below)

– Multi Mineral Complex without Iron – Klaire Labs 100 vcaps

– Multi Trace Minerals – Pure Encapsulations 60 vcaps (trace elements)

– Vitamin B6 – P-5-P Plus Magnesium – Klaire Labs 100 vcaps

Doses and order of administration of supplementation with attention to the symptoms of "hypermethylation" will be discussed personally.

Introduce a complex of minerals into the diet, in forms that are well absorbed in the intestines.

As you have already correctly noted, for conception and during pregnancy, "megadoses" of vit B12/folate must be administered in the forms of methylfolate (NOT folic acid), methylcobalamin (NOT cyanocobalamin).

Inform your loved ones, especially if there are homozygotes, to do the same genetic tests, especially I would pay attention to children, that is, if you had children, but mom and dad will also not interfere.

If you are pregnant, work with a gynecologist who either understands these methylation cycle mutations himself or works with a geneticist who in turn understands the "response of genes to dietary components." And this is especially if you already, other girls, not you, M……., had such problems as “miscarriage”, “missed pregnancy”, etc.

And as always, yes, “Sveta’s song” (actually a collapse of research on gluten / casein and autoimmune diseases, my personal practical experience and my many colleagues from the USA), exclude sources of GLUTEN and especially wheat, reduce animal milk to almost “no ”, or use, NOT systematically, and less allergenic (raw goat milk and products from it, but on the basis of a rotational diet).

Give preference to whole foods, not semi-finished products and corporate “mashups”, like salad “olivier” or “herring under a fur coat”, mushroom soup, pita bread with cheese in a Georgian restaurant, etc.

Introduce vegetable / fruit juices, green smoothies into your diet, be sure and ONLY homemade.

Drink enough pure water.

Introduce vitamin C into your diet.

Start detox procedures, even if very simple, but working, like yoga at least 3 times a week (you can also hot), high-intensity exercise - short intervals, saunas, anything that helps to sweat.

Put filters on the shower to minimize the amount of chlorine in your body.

Make snacks between meals protein, not carbohydrate.

Try to eat in small portions, if snacking is necessary, or you are in the process of "green smoothies", juices / proteins / amino acids, then you will most likely get 4-5 meals, BUT, there should be intervals of at least 3.5 -4 hours between meals . Approaches to nutrition and frequency, quantity are very individual, depending on many things: metabolic type, already accompanying diagnoses, polymorphisms of other genes / genetic predispositions, physical lifestyle, your goals, etc. Therefore, I am now talking about you.

Never, under any pretext, use a microwave and in restaurants ask if a microwave was used to prepare your dish. Reputable restaurants don't even have them.

Many aspects of the lifestyle are already well known to you personally, but it is still better to place accents in your approaches.

Health!

Sincerely, Doc. Lana.

Posted in

Is it possible to give birth to a healthy child if the mother has a mutation in the MTHFR gene? and got the best answer

Answer from Nightbird[guru]
A mother's mutation in the MTHFR gene is NOT a SENTENCE.
There may be mutations in different places, by the way.
When a mutant MTHFR gene is detected in a heterozygous state*, there are no good reasons for fear. As a preventive measure for hypercoagulable conditions, it is recommended to take folic acid 0.4 mg / day in two doses daily during pregnancy, eat well and examine the hemostasiogram once every three months (or according to indications).
The most common enzyme defect that is associated with a moderate increase in HC (homocysteine) levels is a mutation in the gene encoding MTHFR. MTHFR catalyzes the conversion of folic acid to its active form. To date, 9 mutations of the MTHFR gene located at the 1p36.3 locus have been described. The most common of them is the C677T substitution (in the MTHFR protein - the substitution of alanine for valine), which is manifested by thermolability and a decrease in the activity of the MTHFR enzyme. It has been observed that an increase in the content of folate in food can prevent an increase in the concentration of HC in plasma.
An increase in the level of homocysteine in the blood plasma directly correlates with the inhibition of thrombomodulin synthesis, a decrease in the activity of AT-III and endogenous heparin, and also with the activation of the production of thromboxane A2. In the future, such changes cause microthrombosis and microcirculation disorders, which, in turn, plays a significant role in the pathology of the spiral arteries and the development of obstetric complications associated with changes in the uteroplacental circulation.
The reason for the elevated blood homocysteine level: C677T variant in the MTHFR gene is a mutation in the gene for the enzyme methylenetetrahydrofolate reductase.
The replacement of cytosine with thymine at position 677 leads to a decrease in the functional activity of the enzyme to 35% of the average value.
Polymorphism data:
*frequency of occurrence of homozygotes in the population - 10-12%
* frequency of occurrence of heterozygotes in the population - 40%
....
Carriers of the T variant are deficient in folic acid during pregnancy, leading to neural tube defects in the fetus.
Smoking exacerbates the effects of the 677T variant....
The appointment of folic acid can significantly reduce the risk of the consequences of this variant of the polymorphism.
more details here --
In general, who will be taken where ... It is impossible to say for sure. It also depends on the father - what is in his genome !!!
Try asking your question in more detail here --
Or even better here --
GOOD LUCK!

(from lat. recessus - retreat, removal)

one of the forms of phenotypic expression of genes. When crossing individuals that differ in a certain trait, G. Mendel found that in hybrids of the first generation, one of the parental traits disappears (recessive), and the other appears (dominant) (see Mendelism, Mendel's laws). The dominant form (allele (See Alleles)) of the gene (A) manifests its effect in homo- and heterozygous states (AA, Aa), while the recessive allele (a) can appear only in the absence of the dominant (-a) (see Heterozygosity, homozygosity). That. , a recessive allele is a repressed member of an allelic pair of genes. Dominance or R. alleles are revealed only during the interaction of a specific pair of allelic genes. This can be traced when analyzing a gene that occurs in several states (the so-called multiple allele series). A rabbit, for example, has a series of 4 genes that determine the color of the coat (C - solid color, or agouti; cch - chinchilla; ch - Himalayan color; c - albino). If the rabbit has the Ccch genotype, then in this combination cch is a recessive allele, and in combinations cchch and cchc it dominates, causing the color of the chinchilla.

The nature of the manifestation of a recessive trait may change under the influence of external conditions. So, Drosophila has a recessive mutation (See Mutations) - “rudimentary wings”, which in the homozygous at the optimum temperature (25 ° C) leads to a sharp decrease in the size of the wings. When the temperature rises to 30 ° C, the size of the wings increases and can reach the norm, i.e., appear as a dominant trait.

The recessive effect of a gene may be due to a slowdown or change in the course of any biochemical function. A significant part of congenital metabolic disorders in humans is inherited in a recessive manner, i.e., the clinical picture of the disease is observed only in homozygotes. In heterozygotes, the disease does not manifest itself due to the functioning of the normal (dominant) allele (see "Molecular diseases", Hereditary diseases). Most recessive lethal mutations are associated with a violation of vital biochemical processes, which leads to the death of individuals homozygous for this gene. Therefore, in the practice of livestock and crop production, it is important to identify individuals that carry recessive lethal and semi-lethal mutations so as not to involve harmful genes in the selection process. The effect of inbreeding depression during inbreeding (see Inbreeding) is associated with the transition of harmful recessive genes to the homozygous state and the manifestation of their action. At the same time, in breeding practice, recessive mutations often serve as valuable starting material. Thus, their use in breeding minks made it possible to obtain animals with skins of platinum, sapphire and other colors, which are often valued more than wild-type dark brown minks.

When conducting genetic analysis, a hybrid is crossed with a parental form that is homozygous for recessive alleles. So it is possible to find out hetero- or homozygosity for the analyzed pairs of genes. Recessive mutations play an important role in the evolutionary process. The Soviet geneticist S. S. Chetverikov showed (1926) that natural populations contain a huge number of various recessive mutations in the heterozygous state. Wed Dominance, Codominance.

What is there to say? ? Only in the homozygote does it manifest itself when both chromosomes with this recessive trait meet ... In heterozygotes of his generations, the dominant "strangles" until both recessives meet.

Homozygous mutation MTHFR (C677 T) (note to self)

677T mutation and other pregnancy complications

Women with the 677TT genotype are prone to developing a vitamin deficiency in folic acid. In non-pregnant women homozygous for this allele, folate deficiency may be found only in erythrocytes, and plasma folate levels may not be affected. However, during pregnancy in homozygous women, there is a decrease in the concentration of folates not only inside the erythrocytes, but also in the blood plasma.

Studies have shown an increased risk of developing nephropathy in pregnant women with vascular disease. This is in good agreement with data on the effect of high concentrations of homocysteine in the blood with the risk of developing nephropathy in pregnant women. In addition, it has been shown that the concentration of homocysteine in the blood correlates with the concentration of fibronectin in cells, which indicates an important role of homocysteine in the development of endothelial dysfunction during pregnancy. An increase in the frequency of the 677T allele was noted not only in late toxicosis (preeclampsia), but also in other pregnancy complications (placental abruption, fetal growth retardation, antenatal fetal death). The combination of the 677T allele with other risk factors leads to an increased risk of early miscarriage. Adding folic acid to the diet significantly reduces the risk of pregnancy complications. The prophylactic value of adding folic acid to the diet is especially pronounced in the presence of hyperhomocysteinemia.

Thank you! I just have the mutation MTHFR (C677 T) - TT

Homocysteine was greatly elevated. For a year she took angiovit, Omega-3, chimes. A year later, homocysteine is normal.

Excellent article! Very well written!

Handed over for mutation? And homocysteine?

Year? Wow! I was prescribed angiovit for a month - my homocysteine is 9.776 (4.6 - 8.1). So I have such a mutation .. I read a lot. horror..

yes, I wrote homocysteine above, and mutations - I have just this case: (when T / T, i.e. homozygous mutation (((

And my homocysteine was 17. I went to OTTO to see a hematologist. She told me to take it all the time before pregnancy. And how to get pregnant immediately to her. In general, all your life you need to monitor the level of homocysteine and take these drugs from time to time. Here.

did they say anything about breeding? I just already had one ZB

I also have a mutation in other genes. The doctor said that she thinks that I can’t get pregnant because of this, and it seems to affect the gestation. She said that the blood becomes prone to thrombosis. And if a microthrombus forms, it will damage the pregnancy. Although then my gynecologist showed the tests to another hematologist or even a gynecologist. And that other doctor said don't worry, it's okay, the main thing is to control homocysteine during pregnancy.

I don’t know about blood clots, whether this is due to homocysteine or something else.

Wow. and, unfortunately, this is not all for me .. ((I'm still that mutant!

GE4) Plasminogen activator inhibitor gene PAI-1 (5G/4G) - 4G/5G

GE6) Alpha-2 integrin gene GPIa (C807T) - C/T

(GE10) Gene methionine synthase reductase MTRR (A66G) - A/G

(GE8) MTHFR methylenetetrahydrofolate reductase gene (C677 T) - T/T

GE19) Angiotensin converting factor gene ACE(Ins/Del) - D/D

(GE18) G-protein beta 3 gene GNB3 (C825T) - C/T

GE39) N-acetyl transferase gene (NAT2-4,5,6,7,12 alleles) - *5B/*6

(GE36) Mu-glutathione S-transferase gene (GSTM1 gene deletion) - Del/Del

GE38) Gene pi-glutathione S-transferase (GSTP1) - Ile/Val

(GE43) Cytochrome P450 enzyme gene (CYP1A2*1C,*1F) - *1F/*1F

You nailed genetics!

I understand that you need to see Shablis.

Leeches, hyperbaric chamber, oxygen cocktails, physio - these are our best friends.

Chablis. Who is this? In St. Petersburg? I don’t understand at all, is it possible for a mutant like me to bear a child? Too many mutations

I'm such a mutant!!

homozygous for MTHFR, F7, PLAT

heterozygous for MTRR, GPLA, PAI-1, FGB

there were 2 ZB, and in the second saw and angoivitis and chimes and nothing helped

I am currently undergoing hydrotherapy.

I drink angiovit all the time, as soon as I quit immediately homocysteine rises, in May I took a break for a week, and homocysteine immediately rose to 18, on angiovit 8-11.

I often fall into despair, but somewhere in the depths of my soul I still believe that I will be a mother!! and I wish you good luck!!

Tell.

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[email protected]@@@@, I would take hCG before going to the doctor to see the dynamics or vice versa. Re themselves rivers.

Can I trust the result, because I looked only after 40 minutes? Damn, nerves nerves)

i_sh, at work in the morning, call and tell me the temperature, cough. And then some kind of lingering armor.

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Heterozygous mutation state

Help me please.

An analysis for mutations in the Notch 3 gene (Cadasil syndrome) was carried out by direct automatic sequencing

The mutation c.268C T, Arg90Cys was found in the heterozygous state, described in the HGMD mutation database.

Thank you in advance!

Also do not forget to thank the doctors.

geneticist7 22:07

you need to know what caused the examination, who sent it to him and see the conclusion.

The reason for the examination was my condition in which I got to the clinic. I suddenly developed weakness, there was a loss of speech. In Kazan, I went through all possible tests and examinations. Found: Progressive leukoencephalopathy, probably due to isolated cerebral vasculitis, in the form of moderate cognitive impairment, bulbar syndrome, pyramidal insufficiency. Hyperhomocysteinemia. Hypercholesterolemia. The professor recommended to undergo molecular genetic diagnosis of a mutation in the Notch-3 gene.

I already sent the conclusion of the molecular genetic laboratory in my previous letter.

Doctor, please help me! Decipher this conclusion.

geneticist0 20:31

The analysis confirmed the syndrome that the doctor suspected.

Thank you very much for your answer. Now I know that I'm sick. Until the disease completely took over me. Apparently, it will be later. Well, that's my destiny.

I would like to know, however, what a heterozygous mutation is. Obviously, this somehow affects the principle of inheritance of the disease. I have two children, boys. My sister has two girls. She is younger than me, she is 38 years old. I'm 44 years old. I inherited the disease from my father. He died at 61. The cause of death was a stroke. His younger brother and older sister are alive and relatively healthy. Their children are also healthy. Really, I'm the only one who got the mutation.

If you answer at least a few of these questions, I will be very grateful to you.

All the best.

geneticist3 10:35

The same probability was for you and your sister. Since she is younger than you, it is not yet known if she inherited.

Your sister and your children can have the same genetic analysis that was done for you. If they want to know now whether they have inherited the mutation or not.

what is a homozygous mutation

Homozygosity and heterozygosity, dominance and recessiveness.

Homozygosity (from the Greek "homo" equal, "zygote" fertilized egg) a diploid organism (or cell) carrying identical alleles in homologous chromosomes.

Gregor Mendel was the first to establish a fact indicating that plants that are similar in appearance can differ sharply in hereditary properties. Individuals that do not split in the next generation are called homozygous. Individuals in whose offspring a splitting of traits is found are called heterozygous.

Homozygosity is a state of the hereditary apparatus of an organism in which homologous chromosomes have the same form of a given gene. The transition of a gene to a homozygous state leads to the manifestation in the structure and function of the organism (phenotype) of recessive alleles, the effect of which, when heterozygous, is suppressed by dominant alleles. The test for homozygosity is the absence of segregation in certain types of crossing. A homozygous organism produces only one type of gamete for this gene.

Heterozygosity is a condition inherent in any hybrid organism in which its homologous chromosomes carry different forms (alleles) of a particular gene or differ in the relative position of the genes. The term "heterozygosity" was first introduced by the English geneticist W. Batson in 1902. Heterozygosity occurs when gametes of different quality in terms of gene or structural composition merge into a heterozygote. Structural heterozygosity occurs when a chromosomal rearrangement of one of the homologous chromosomes occurs, it can be detected in meiosis or mitosis. Heterozygosity is detected by analyzing crosses. Heterozygosity, as a rule, is a consequence of the sexual process, but may result from a mutation. With heterozygosity, the effect of harmful and lethal recessive alleles is suppressed by the presence of the corresponding dominant allele and is manifested only when this gene passes into the homozygous state. Therefore, heterozygosity is widespread in natural populations and is, apparently, one of the causes of heterosis. The masking effect of dominant alleles in heterozygosity is the reason for the preservation and spread of harmful recessive alleles in the population (the so-called heterozygous carriage). Their identification (for example, by testing producers by offspring) is carried out in any breeding and selection work, as well as in the preparation of medical genetic forecasts.

In our own words, we can say that in breeding practice, the homozygous state of the genes is called “correct”. If both alleles that control any characteristic are the same, then the animal is called homozygous, and in breeding by inheritance will pass exactly this characteristic. If one allele is dominant and the other is recessive, then the animal is called heterozygous, and will outwardly demonstrate a dominant characteristic, and inherit either a dominant characteristic or a recessive one.

Any living organism has a section of DNA (deoxyribonucleic acid) molecules called chromosomes. During reproduction, germ cells carry out copying of hereditary information by their carriers (genes), which make up a section of chromosomes that have the shape of a spiral and are located inside the cells. Genes located in the same loci (strictly defined positions in the chromosome) of homologous chromosomes and determining the development of any trait are called alleles. In a diploid (double, somatic) set, two homologous (identical) chromosomes and, accordingly, two genes just carry the development of these different traits. When one trait predominates over another, it is called dominance, and the genes are dominant. A trait whose expression is suppressed is called recessive. The homozygosity of an allele is the presence in it of two identical genes (carriers of hereditary information): either two dominant or two recessive. The heterozygosity of an allele is the presence of two different genes in it, i.e. one is dominant and the other is recessive. Alleles that in a heterozygote give the same manifestation of any hereditary trait as in a homozygote are called dominant. Alleles that show their effect only in the homozygote, and are invisible in the heterozygote, or are suppressed by the action of another dominant allele, are called recessive.

The principles of homozygosity, heterozygosity and other foundations of genetics were first formulated by the founder of genetics, Abbot Gregor Mendel, in the form of his three laws of inheritance.

Mendel's first law: "Offspring from crossing individuals homozygous for different alleles of the same gene are uniform in phenotype and heterozygous in genotype."

Mendel's second law: "When heterozygous forms are crossed, a regular splitting is observed in the offspring in a ratio of 3: 1 by phenotype and 1: 2: 1 by genotype."

Mendel's third law: “The alleles of each gene are inherited regardless of the body size of the animal.

From the point of view of modern genetics, his hypotheses look like this:

1. Each trait of a given organism is controlled by a pair of alleles. An individual that received the same alleles from both parents is called homozygous and is indicated by two identical letters (for example, AA or aa), and if it receives different ones, then heterozygous (Aa).

2. If an organism contains two different alleles of a given trait, then one of them (dominant) can manifest itself, completely suppressing the manifestation of the other (recessive). (The principle of dominance or uniformity of the descendants of the first generation). As an example, let's take a monohybrid (only on the basis of color) crossing in cockers. Let's assume that both parents are homozygous for color, so a black dog will have a genotype, which we will designate as AA for example, and a fawn aa. Both individuals will produce only one type of gamete: black only A, and fawn only a. No matter how many puppies are born in such a litter, they will all be black, since the black color is dominant. On the other hand, they will all be carriers of the fawn gene, since their genotype is Aa. For those who have not figured it out too much, we note that the recessive trait (in this case, the fawn color) appears only in the homozygous state!

3. Each sex cell (gamete) receives one of each pair of alleles. (Principle of splitting). If we cross the descendants of the first generation or any two cockers with the Aa genotype, splitting will be observed in the offspring of the second generation: Aa + aa \u003d AA, 2Aa, aa. Thus, the splitting by phenotype will look like 3:1, and by genotype as 1:2:1. That is, when mating two black heterozygous Cockers, we can have 1/4 the probability of producing black homozygous dogs (AA), 2/4 the probability of producing black heterozygotes (Aa) and 1/4 the probability of producing fawn (aa). In life, everything is not so simple. Sometimes two black heterozygous Cockers can produce 6 fawn puppies, or they can all be black. We simply calculate the probability of the appearance of this trait in puppies, and whether it will manifest itself depends on which alleles got into the fertilized eggs.

4. During the formation of gametes, any allele from one pair can get into each of them along with any other from another pair. (Principle of independent distribution). Many traits are inherited independently, for example, if the color of the eyes may depend on the general color of the dog, then it is practically not related to the length of the ears. If we take a dihybrid cross (according to two different traits), then we can see the following ratio: 9: 3: 3: 1

5. Each allele is passed down from generation to generation as a discrete unchanging unit.

b. Each organism inherits one allele (for each trait) from each parent.

If for a specific gene the two alleles carried by an individual are the same, which one will predominate? Since the mutation of alleles often results in a loss of function (null alleles), an individual carrying only one such allele will also have the "normal" (wild type) allele for the same gene; a single normal copy will often be sufficient to maintain normal function. For an analogy, let's imagine we're building a brick wall, but one of our two regular contractors is on strike. As long as the remaining supplier can supply us with enough bricks, we can continue to build our wall. Geneticists call this phenomenon, when one of the two genes can still provide normal function, dominance. The normal allele is determined to be dominant over the abnormal allele. (In other words, the wrong allele can be said to be recessive to the normal one.)

When one speaks of a genetic abnormality "carried" by an individual or line, it is meant that there is a mutated gene that is recessive. If we do not have sophisticated testing to directly detect this gene, then we will not be able to visually determine the courier (carrier) from an individual with two normal copies (alleles) of the gene. Unfortunately, lacking such testing, the courier will not be detected in time and will inevitably pass on the mutation allele to some of its offspring. Each individual can be similarly "staffed" and carry several of these dark secrets in their genetic baggage (genotype). However, we all have thousands of different genes for many different functions, and as long as these abnormalities are rare, the likelihood that two unrelated individuals carrying the same "abnormality" will meet to reproduce is very low.

Sometimes individuals with a single normal allele may have an "intermediate" phenotype. For example, in the Basenji, which carries one allele for pyruvate kinase deficiency (an enzyme deficiency leading to mild anemia), the average lifespan of a red blood cell is 12 days. This is an intermediate type between a normal cycle of 16 days and a cycle of 6.5 days in a dog with two incorrect alleles. Although this is often called incomplete dominance, in this case it would be preferable to say that there is no dominance at all.

Let's take our brick wall analogy a little further. What if a single supply of bricks isn't enough? We'll be left with a wall that's lower (or shorter) than the intended one. Will it matter? It depends on what we want to do with the "wall" and possibly genetic factors. The result may not be the same for the two people who built this wall. (A low wall may keep floods out, but not floods!) If there is a possibility that an individual carrying only one copy of the wrong allele will exhibit it with the wrong phenotype, then that allele should be regarded as dominant. Her refusal to always do so is defined by the term penetrance.

A third possibility is that one of the contractors is supplying us with custom bricks. Not realizing this, we continue to work - as a result, the wall falls. We could say that defective bricks are the dominant factor. Success in understanding several dominant genetic diseases in humans suggests that this is a reasonable analogy. Most dominant mutations affect proteins that are components of large macromolecular complexes. These mutations result in proteins that cannot interact properly with other components, leading to the failure of the entire complex (defective bricks - a fallen wall). Others are found in regulatory sequences adjacent to genes and cause the gene to be transcribed at the wrong time and place.

Dominant mutations can persist in populations if the problems they cause are subtle and not always pronounced, or appear at a mature stage of life after the affected individual has participated in reproduction.

A recessive gene (i.e., a trait determined by it) may not appear in one or many generations until two identical recessive genes from each parent meet (the sudden manifestation of such a trait in offspring should not be confused with a mutation).

Dogs that have only one recessive gene - the determinant of any trait, will not show this trait, since the action of the recessive gene will be masked by the manifestation of the influence of the dominant gene paired with it. Such dogs (carriers of a recessive gene) can be dangerous for the breed if this gene determines the appearance of an undesirable trait, because it will pass it on to their descendants, and they will continue to do so in the breed. If you accidentally or thoughtlessly pair two carriers of such a gene, they will give part of the offspring with undesirable traits.

The presence of a dominant gene is always clearly and outwardly manifested by the corresponding feature. Therefore, dominant genes that carry an undesirable trait are much less dangerous for the breeder than recessive ones, since their presence always appears, even if the dominant gene "works" without a partner (Aa).

But apparently, to complicate matters, not all genes are absolutely dominant or recessive. In other words, some are more dominant than others and vice versa. For example, some factors that determine coat color can be dominant, but still not outwardly manifest unless they are supported by other genes, sometimes even recessive ones.

Matings do not always give ratios exactly as expected average results, and a large litter or a large number of offspring in multiple litters must be produced to obtain a reliable result from a given mating.

Some external traits may be "dominant" in some breeds and "recessive" in others. Other traits may be due to multiple genes or semi-genes that are not simple dominants or Mendelian recessives.

Diagnosis of genetic disorders

Diagnosis of genetic disorders as a doctrine of recognition and designation of genetic diseases consists mainly of two parts

identification of pathological signs, that is, phenotypic abnormalities in individual individuals; proof of the heritability of the detected deviations. The concept of "assessment of genetic health" means checking a phenotypically normal individual to identify unfavorable recessive alleles (heterozygosity test). Along with genetic methods, methods are also used that exclude the influence of the environment. Routine research methods: evaluation, laboratory diagnostics, methods of pathological anatomy, histology and pathophysiology. Special methods of great importance are cytogenetic and immunogenetic methods. The cell culture method has contributed to significant advances in the diagnosis and genetic analysis of hereditary diseases. In a short time, this method made it possible to study about 20 genetic defects found in humans (Rerabek and Rerabek, 1960; New, 1956; Rapoport, 1969) with its help it is possible in many cases to differentiate homozygotes from heterozygotes with a recessive type of inheritance

Immunogenetic methods are used to study blood groups, blood serum and milk proteins, seminal fluid proteins, types of hemoglobin, etc. The discovery of a large number of protein loci with multiple alleles led to a "renaissance" in Mendelian genetics. Protein loci are used:

to establish the genotype of individual animals

when examining some specific defects (immunoparesis)

to study linkage (genes markers)

for genetic incompatibility analysis

to detect mosaicism and chimerism

The presence of a defect from the moment of birth, defects that appear in certain lines and nurseries, the presence of a common ancestor in each abnormal case - does not mean the heredity of this condition and the genetic nature. When a pathology is detected, it is necessary to obtain evidence of its genetic conditionality and determine the type of inheritance. Statistical processing of the material is also necessary. Genetic-statistical analysis is subjected to two groups of data:

Population data - frequency of congenital anomalies in the cumulative population, frequency of congenital anomalies in the subpopulation

Family data - proof of genetic conditioning and determination of the type of inheritance, inbreeding coefficients and the degree of concentration of ancestors.

When studying genetic conditioning and type of inheritance, the observed numerical ratios of normal and defective phenotypes in the offspring of a group of parents of the same (theoretically) genotype are compared with splitting ratios calculated on the basis of binomial probabilities according to Mendel's laws. To obtain statistical material, it is necessary to calculate the frequency of affected and healthy individuals among the blood relatives of the proband over several generations, determine the numerical ratio by combining individual data, combine data on small families with correspondingly identical parental genotypes. Also important is information about the size of the litter and the sex of the puppies (to assess the possibility of sex-linked or sex-limited heredity).

In this case, it is necessary to collect data for the selection:

Complex selection - a random sample of parents (used when checking a dominant trait)

Purposeful selection - all dogs with a "bad" sign in the population after a thorough examination of it

Individual selection - the probability of an anomaly is so low that it occurs in one puppy from a litter

Multiple selection - intermediate between purposeful and individual, when there is more than one affected puppy in the litter, but not all of them are probands.

All methods, except for the first one, exclude the mating of dogs with the Nn genotype, which do not give anomalies in the litters. There are various ways to correct data: N.T.J. Bailey (79), L.L. Kavaii-Sforza and V.F. Bodme and K. Stehr.

Genetic characterization of a population begins with an estimate of the prevalence of the disease or trait under study. These data are used to determine the frequencies of genes and corresponding genotypes in the population. The population method makes it possible to study the distribution of individual genes or chromosomal abnormalities in populations. To analyze the genetic structure of a population, it is necessary to examine a large group of individuals, which must be representative, allowing one to judge the population as a whole. This method is informative in the study of various forms of hereditary pathology. The main method in determining the type of hereditary anomalies is the analysis of pedigrees within the related groups of individuals in which cases of the studied disease were recorded according to the following algorithm:

Determination of the origin of anomalous animals by breeding cards;

Drawing up pedigrees for anomalous individuals in order to search for common ancestors;

Analysis of the type of inheritance of the anomaly;

Carrying out genetic and statistical calculations on the degree of randomness of the appearance of an anomaly and the frequency of occurrence in the population.

The genealogical method for analyzing pedigrees occupies a leading position in genetic studies of slowly breeding animals and humans. By studying the phenotypes of several generations of relatives, it is possible to establish the nature of the inheritance of the trait and the genotypes of individual family members, to determine the likelihood of manifestation and the degree of risk for offspring for a particular disease.

When determining a hereditary disease, attention is paid to the typical signs of a genetic predisposition. Pathology occurs more often in a group of related animals than in the whole population. This helps to distinguish a congenital disease from a breed predisposition. However, analysis of the pedigree shows that there are familial cases of the disease, which suggests the presence of a particular gene or group of genes responsible for it. Secondly, a hereditary defect often affects the same anatomical region in a group of related animals. Thirdly, with inbreeding, there are more cases of the disease. Fourth, hereditary diseases often present early and often have a constant age of onset.

Genetic diseases usually affect a few animals in a litter, as opposed to intoxication and infectious diseases that affect the entire litter. Congenital diseases are very diverse, from relatively benign to invariably fatal. Diagnosis is usually based on history taking, clinical signs, history of illness in related animals, results of test crosses, and certain diagnostic tests.

A significant number of monogenic diseases are inherited in a recessive manner. This means that with the autosomal localization of the corresponding gene, only homozygous mutation carriers are affected. Mutations are most often recessive and appear only in the homozygous state. Heterozygotes are clinically healthy, but are equally likely to pass on the mutant or normal version of the gene to their children. Thus, for a long time, a latent mutation can be passed from generation to generation. With an autosomal recessive type of inheritance in the pedigrees of seriously ill patients who either do not live to reproductive age, or have a sharply reduced potency for reproduction, it is rarely possible to identify sick relatives, especially in the ascending line. The exception is families with a high level of inbreeding.

Dogs that have only one recessive gene - the determinant of any trait, will not show this trait, since the action of the recessive gene will be masked by the manifestation of the influence of the dominant gene paired with it. Such dogs (carriers of a recessive gene) can be dangerous for the breed if this gene determines the appearance of an undesirable trait, because it will pass it on to their descendants. If you accidentally or deliberately pair two carriers of such a gene, they will give part of the offspring with undesirable traits.

The expected ratio of splitting offspring according to one trait or another is approximately justified with a litter of at least 16 puppies. For a litter of normal size puppies, one can only talk about a greater or lesser probability of a trait determined by a recessive gene for the offspring of a certain pair of sires with a known genotype.

The selection of recessive anomalies can be carried out in two ways. The first of these is to exclude from breeding dogs with manifestations of anomalies, i.e., homozygotes. The occurrence of an anomaly with such selection in the first generations decreases sharply, and then more slowly, remaining at a relatively low level. The reason for the incomplete elimination of some anomalies even during a long and stubborn selection is, firstly, a much slower reduction in carriers of recessive genes than homozygotes. Secondly, in the fact that with mutations that slightly deviate from the norm, breeders do not always discard abnormal dogs and carriers.

With an autosomal recessive type of inheritance:

A trait can be passed down through generations even with a sufficient number of offspring

The trait may appear in children in the (apparent) absence of it in the parents. Found then in 25% of cases in children

The trait is inherited by all children if both parents are sick

A sign in 50% develops in children if one of the parents is sick

Male and female offspring inherit this trait equally.

Thus, the absolutely complete elimination of the anomaly is possible in principle, provided that all carriers are identified. The scheme of such detection: heterozygotes for recessive mutations can in some cases be detected by laboratory research methods. However, for the genetic identification of heterozygous carriers, it is necessary to conduct analyzing crosses - mating a suspected carrier dog with a homozygous abnormal (if the anomaly slightly affects the body) or with a previously established carrier. If, among others, abnormal puppies are born as a result of such crosses, the tested sire is clearly identified as a carrier. However, if such puppies were not identified, then an unambiguous conclusion cannot be made on a limited sample of the obtained puppies. The probability that such a sire is a carrier decreases with the expansion of the sample - an increase in the number of normal puppies born from matings with him.

At the Department of the Veterinary Academy of St. Petersburg, an analysis of the structure of the genetic load in dogs was carried out and it was found that the largest proportion - 46.7% are anomalies inherited according to a monogenic autosomal recessive type; anomalies with complete dominance amounted to 14.5%; 2.7% of anomalies appeared as non-full-dominant signs; 6.5% of anomalies are inherited as sex-linked, 11.3% of hereditary traits with a polygenic type of inheritance, and 18%3% of the entire spectrum of hereditary anomalies, the type of inheritance has not been established. The total number of anomalies and diseases with a hereditary basis in dogs was 186 items.

Along with the traditional methods of selection and genetic prevention, the use of phenotypic markers of mutations is relevant.

Genetic disease monitoring is a direct method for assessing hereditary diseases in the offspring of unaffected parents. "Sentinel" phenotypes can be: cleft palate, cleft lip, inguinal and umbilical hernias, dropsy of newborns, convulsions in newborn puppies. In monogenic fixed diseases, it is possible to identify the actual carrier through the marker gene associated with it.

The existing breed diversity of dogs presents a unique opportunity to study the genetic control of numerous morphological traits, the various combinations of which determine breed standards. An illustration of this situation can serve as two of the currently existing breeds of domestic dogs, contrastingly different from each other at least in such morphological features as height and weight. This is the English Mastiff breed, on the one hand, whose representatives have a height at the withers of up to 80 cm and a body weight of more than 100 kg, and the Chi Hua Hua breed, 30 cm and 2.5 kg.

The process of domestication involves the selection of animals for their most outstanding traits, from a human point of view. Over time, when the dog began to be kept as a companion and for its aesthetic appearance, the direction of selection changed to obtaining breeds poorly adapted to survival in nature, but well adapted to the human environment. There is an opinion that "mongrels" are healthier than purebred dogs. Indeed, hereditary diseases are probably more common in domestic animals than in wild ones.

“One of the most important goals is to develop methods for combining the tasks of improving animals according to breeding traits and maintaining their fitness at the required level - as opposed to one-sided selection that is dangerous for the biological well-being of domesticated organisms for the maximum (sometimes exaggerated, excessive) development of specific breed traits” - (Lerner, 1958).

The effectiveness of selection, in our opinion, should consist in diagnosing anomalies in affected animals and identifying carriers with defective heredity, but with a normal phenotype. Treatment of affected animals in order to correct their phenotypes can be considered not only as a measure to improve the aesthetic appearance of animals (oligodontia), but also to prevent cancer (cryptorchidism), maintain biological, full-fledged activity (hip dysplasia) and stabilize health in general. In this regard, selection against anomalies is necessary in the joint activities of cynology and veterinary medicine.

The ability to test DNA for various dog diseases is a very new thing in canine science, knowing this can alert breeders to which genetic diseases to look out for when matching sire pairs. Good genetic health is very important because it determines a dog's biologically fulfilling life. Dr. Padgett's book, Hereditary Disease Control in Dogs, shows how to read a genetic lineage for any abnormality. Genetic pedigrees will show whether the disease is sex-linked, inherited through a simple dominant gene, or through a recessive one, or whether the disease is polygenic in origin. Unintentional genetic errors will occur from time to time regardless of the care taken by the breeder. Using genetic lineages as a vehicle for knowledge sharing, it is possible to dilute "harmful" genes to the point of stopping them from appearing until a DNA marker is found to test for their transmission. Since the selection process involves the improvement of the population in the next generation, it is not the phenotypic characteristics of the direct elements of the breeding strategy (individuals or pairs of crossed individuals) that are taken into account, but the phenotypic characteristics of their descendants. It is in connection with this circumstance that the need arises to describe the inheritance of a trait for selection problems. A pair of interbreeding individuals differ from the rest of the same individuals in their origin and phenotypic characteristics of the trait, both themselves and their relatives. Based on these data, if there is a ready description of inheritance, it is possible to obtain the expected characteristics of the offspring and, therefore, estimates of the breeding values of each of the elements of the breeding strategy. In any action taken against any genetic anomaly, the first step is to determine the relative importance of the "bad" trait compared to other traits. If the undesirable trait has a high heritability and causes serious damage to the dog, you should proceed differently than if the trait is rare or of minor importance. A dog of excellent breed type that transmits a faulty color remains a much more valuable sire than a mediocre one with the correct color.

There may be mutations in different places, by the way.

When a mutant MTHFR gene is detected in a heterozygous state*, there are no good reasons for fear. As a preventive measure for hypercoagulable conditions, it is recommended to take folic acid 0.4 mg / day in two doses daily during pregnancy, eat well and examine the hemostasiogram once every three months (or according to indications).

The most common enzyme defect that is associated with a moderate increase in HC (homocysteine) levels is a mutation in the gene encoding MTHFR. MTHFR catalyzes the conversion of folic acid to its active form. To date, 9 mutations of the MTHFR gene located at the 1p36.3 locus have been described. The most common of them is the C677T substitution (in the MTHFR protein - the substitution of alanine for valine), which is manifested by thermolability and a decrease in the activity of the MTHFR enzyme. It has been observed that an increase in the content of folate in food can prevent an increase in the concentration of HC in plasma.

An increase in the level of homocysteine in the blood plasma directly correlates with the inhibition of thrombomodulin synthesis, a decrease in the activity of AT-III and endogenous heparin, and also with the activation of the production of thromboxane A2. In the future, such changes cause microthrombosis and microcirculation disorders, which, in turn, plays a significant role in the pathology of the spiral arteries and the development of obstetric complications associated with changes in the uteroplacental circulation. link

The reason for the elevated blood homocysteine level: C677T variant in the MTHFR gene is a mutation in the gene for the enzyme methylenetetrahydrofolate reductase.

The replacement of cytosine with thymine at position 677 leads to a decrease in the functional activity of the enzyme to 35% of the average value.

Polymorphism data:

*frequency of occurrence of homozygotes in the population - 10-12%

* frequency of occurrence of heterozygotes in the population - 40%

Carriers of the T variant are deficient in folic acid during pregnancy, leading to neural tube defects in the fetus.

Smoking exacerbates the effects of the 677T variant.

The appointment of folic acid can significantly reduce the risk of the consequences of this variant of the polymorphism.

In general, who will be taken where ... It is impossible to say for sure. It also depends on the father - what is in his genome.

Try asking your question in more detail here - link

Everything is in the power of God. Here the statistics are powerless.