What are the features of the linked type of inheritance. X-linked dominant inheritance

An X-linked recessive disease (or symptom) always manifests itself in men with the corresponding gene, and in women only in cases of

a mozygotic state (which is extremely rare).

An example of an X-linked recessive disease is hemophilia A, characterized by impaired blood clotting due to a deficiency of factor VIII - antihemophilic globulin A. The pedigree of a patient with hemophilia is shown in Fig. IX.11. Clinically, the disease is manifested by frequent prolonged bleeding, even with a minor wound, hemorrhages in organs and tissues. The incidence of the disease is 1 in 10,000 newborn boys. Using the above notation, it is possible to determine all possible genotypes in the offspring of a sick man and a healthy woman (Fig. IX. 12).

According to the scheme, all children will be phenotypically healthy, but genotypically all daughters are carriers of the hemophilia gene. If a woman, a carrier of the hemophilia gene, marries a healthy man, the following variants of the genotypes of the offspring are possible (Fig. IX. 13).

Daughters in 50% of cases will be carriers of the pathological gene, and for sons there is a 50% risk of being sick with hemophilia.

Thus, the main features of X-linked recessive inheritance are as follows:

1) the disease occurs mainly in males;

2) the trait (disease) is transmitted from a sick father through his phenotypically healthy daughters to half of his grandchildren;

3) the disease is never transmitted from father to son;

4) carriers sometimes show subclinical signs of pathology.

More on the topic Recessive X-linked type of inheritance of the disease:

1. 1. Ideas about heredity, variability, kinship, norm and deviation in the pre-scientific period.

Genes localized on the X chromosome, as in autosomal inheritance, can be dominant and recessive. The main feature of X-linked inheritance is the lack of transmission of the corresponding gene from the father to the son, because men, being hemizygous (have only one X chromosome), pass on their X chromosome only to their daughters.

If a dominant gene is localized on the X chromosome, this type of inheritance is called X-linked dominant. It is characterized by the following signs:

If the father is sick, then all the daughters will be sick, and all the sons will be healthy;

Sick children appear only if one of the parents is sick;

With healthy parents, all children will be healthy;

The disease can be traced back to every generation;

If the mother is sick, then the probability of having a sick child is 50%, regardless of gender;

Both men and women are ill, but in general there are 2 times more sick women in the family than sick men.

When a recessive gene is localized on the X chromosome, the type of inheritance is called X-linked recessive. Women are almost always phenotypically healthy (carriers), i.e. heterozygotes. The severity of the disease depends on the degree of damage to the reproductive system. This type of inheritance is characterized by:

The disease affects mainly males;

The disease is observed in male relatives of the proband on the maternal side;

A son never inherits a disease from his father;

If a proband is a sick woman, her father is necessarily sick, and all her sons are also affected;

In a marriage between sick men and healthy homozygous women, all children will be healthy, but daughters may have sick sons;

In a marriage of a sick man and a woman who is a carrier of a daughter: 50% are sick, 50% are carriers; sons: 50% - sick, 50% - healthy.

In a marriage between a healthy man and a heterozygous woman, the probability of having a sick child is 50% for boys and 0% for girls.

Carrier sisters have 50% of sick sons and 50% of carrier daughters.

Pedigree with X-recessive inheritance

Pedigree with X-dominant inheritance

Y-linked inheritance type

In rare cases, there is a paternal or Dutch type of inheritance, due to the presence of mutations in the genes of the Y-chromosome.

At the same time, only men get sick and transmit their disease to their sons through the Y chromosome. Unlike autosomes and the X chromosome, Y chromosome carries relatively few genes (according to the latest data from the international catalog of genes OMIM, only about 40).

A small part of these genes are homologous to the genes of the X chromosome, the rest, which are present only in males, are involved in the control of sex determination and spermatogenesis. Thus, the Y chromosome contains the SRY and AZF genes, which are responsible for the sexual differentiation program.

Mutations in any of these genes result in impaired testicular development and blockage of spermatogenesis, resulting in azoospermia. Such men suffer from infertility, and therefore their disease is not inherited. Men who complain of infertility should be screened for mutations in these genes. Mutations in one of the genes located on the Y chromosome are responsible for some forms of ichthyosis (fish skin), and a completely harmless sign is the hairiness of the auricle.

The sign is transmitted through the male line. The Y chromosome contains genes that are responsible for the hair growth of the auricle, spermatogenesis (azoospermia), the growth rate of the body, limbs, and teeth.

Pedigree with Y-linked inheritance

More than 370 diseases linked (or presumably linked) to the X chromosome have been described. The severity of the disease depends on gender. Full forms of the disease are manifested mainly in men, since they are hemizygous for genes localized on the X chromosome. If the mutation affects a recessive X-linked gene (XR disease), then heterozygous women are healthy, but carriers of the gene (and homozygotes are in most cases lethal). If the mutation affects the dominant X-linked gene (XD disease), then in heterozygous women the disease manifests itself in a mild form (and homozygotes are lethal). The most important property of diseases linked to the X chromosome is the impossibility of their transmission from father to son (since the son inherits the Y chromosome, not the X chromosome of the father).

The genes that cause X-linked diseases are located on the X chromosome, so such diseases manifest themselves in different ways in individuals of different genders. Since women have two X chromosomes, the manifestation of a mutant gene depends on many factors: a woman is heterozygous or homozygous for the mutant gene, a dominant or recessive mutation. An additional factor is the random nature of inactivation of one X chromosome in the cells of the female body. Men have only one X chromosome, so their mutation often manifests itself completely, regardless of whether it is a dominant mutation in women or recessive.

Thus, the terms X-linked dominant or X-linked recessive refer only to the manifestation of the mutation in women. Due to the inactivation of one X chromosome in women, it is difficult to distinguish between dominant and recessive X-linked diseases. And with ornithinecarbamoyltransferase deficiency, often described as an X-linked dominant disease, and Fabry disease, often described as an X-linked recessive disease, heterozygotes often show signs of pathology. In the absence of clear definitions, these diseases should be considered simply as X-linked, without dividing them into recessive and dominant.

This division is more suitable for X-linked diseases in which heterozygotes are usually healthy (for example, Gunther's syndrome) or have the same symptoms as hemizygous males (for example, X-linked hypophosphatemic rickets).

An important feature of X-linked inheritance is that the trait is not transmitted through the male line, since the son receives the Y chromosome from the father. But all daughters of a father with an X-linked disease will inherit the mutant allele, since they necessarily receive this X chromosome from their father.

X-linked dominant inheritance is shown on the example of the pedigree in Fig. 65.21:

There are about twice as many sick women as men.

A sick woman has a 50% chance of transmitting the disease to both sons and daughters.

A sick man transmits the disease only to all daughters.

In women who are heterozygotes, the disease is milder, and its symptoms are more variable than in men.

Sometimes X-linked dominant inheritance occurs in rare diseases that are fatal to male fetuses (Fig. 65.22):

The disease manifests itself only in women who are heterozygous for the mutant gene;

A sick woman has a 50% chance of transmitting the disease to her daughters;

Sick women have an increased likelihood of spontaneous abortions caused by the death of male fetuses.

An example of such a disease is pigment incontinence.

Some X-linked diseases impair reproductive function in women, but for men they are detailed at the stage of intrauterine development, and therefore they arise mainly or exclusively as sporadic diseases in women due to a new mutation. Such diseases include Ecardi's syndrome, Holtz's syndrome and Rett's syndrome.

There is a pseudo-autosomal region on the X chromosome, the genes of which have homologous copies on the Y chromosome and are inherited in the same way as autosomal ones.

As discussed earlier, X-linked phenotype considered dominant if it usually manifests itself in heterozygotes. dominant inheritance can be easily distinguished from autosomal dominant inheritance by the absence of male-to-male transmission, which is clearly impossible with X-linked inheritance, since males pass on the Y chromosome, not the X chromosome to their sons.

Thus, the hallmark of a fully penetrant X-linked dominant pedigree- all daughters of sick men are also sick, while none of the sons is sick; if there is at least one healthy daughter or a sick son, inheritance should be autosomal, not X-linked. Inheritance through a woman does not differ from autosomal dominant inheritance; since women have a pair of X chromosomes, like pairs of autosomes, each child of a sick woman has a 50% chance of inheriting the trait, regardless of gender.

In numerous families with X-linked dominant diseases the clinical picture is usually milder in women, who are almost always heterozygous, since the mutant allele in some of their cells is located on the inactive X chromosome. Thus, most X-linked dominant diseases are not completely dominant, as is the case with most autosomal dominant diseases.

TO X-linked dominant diseases only a few genetic disorders are related. One example is X-linked hypophosphatemic rickets (or vitamin D-resistant rickets), which impairs the ability of the renal tubules to reabsorb phosphate. The defective gene product belongs to the family of endopeptidases that activate or degrade a number of peptide hormones.

The pathogenesis due to which the lack of this endopeptidase causes impairment of phosphate metabolism and rickets, unknown. The disease is classified as X-linked dominant, since, although both sexes are affected, in heterozygous women, serum phosphate levels are less reduced and the clinical picture of rickets is less severe than in sick men.

Characteristics of X-linked dominant inheritance:
Affected men married to a healthy woman do not have sick sons and healthy daughters.
Both sons and daughters of female carriers have a 50% risk of inheriting the phenotype. Pedigree is similar to autosomal dominant inheritance.
Affected women occur almost twice as often as men, but usually have, although variable, but milder manifestations of the phenotype.

Inherent in few forms of pathology, for example, vitamin

D-rickets. The phenotypic manifestation of the disease will have both homozygotes and heterozygotes. Different marriages are genetically possible, but informative are those in which the father will be sick. In a marriage with a healthy woman, the following features of the inheritance of pathologies are observed:

1) all sons and their children will be healthy, since only the Y chromosome can be transferred to them from the father;

2) all daughters will be heterozygous, and phenotypically sick.

With these two features, this type differs from the autosomal dominant type, in which the ratio of sick to healthy siblings is 1: 1 and is the same for children, indistinguishable from those with an autosomal dominant inheritance top (1: 1), and there should be no sex differences either. There is a stronger manifestation of the disease in men, since they do not have the compensating effect of the normal alley. The literature describes pedigrees for some diseases with this type of transmission, which do not have male siblings, since a strong degree of damage causes their intrauterine death. Such a pedigree looks peculiar: there are only women in the offspring, about half of them are sick, the anamnesis may include spontaneous abortions and stillbirths of male fetuses.

The listed types of inheritance involve mainly monogenic diseases (determined by a mutation of one gene). However, the pathological condition may depend on two or more mutant genes. A number of pathological genes have reduced penetrance. Moreover, their presence in the genome, even in a homozygous state, is necessary, but not sufficient for the development of the disease. Thus, not all types of inheritance of human diseases fit into the three schemes listed above.

METHODS FOR DETERMINING PRIMARY BIOCHEMICAL DEFECT.

When considering the history of the discovery of monogenic nosological forms, it is clearly seen that the longest, until about the mid-50s, its period is associated with the isolation of such forms on the basis of clinical and genealogical examination of families. This period, however, is not very productive. For example, currently isolated 18 genetic forms of hereditary mucopolysaccharidoses, caused by mutations of 11-12 different genes, clinically form only two slightly different phenotypes, and on the basis of the clinical picture and the type of inheritance, only two nosological units were discovered - Hurler's syndrome and Hunter's syndrome. The same situation has developed with other classes of hereditary metabolic defects. The discovery and description of hereditary diseases should not be considered complete. Currently, about two thousand mendelian pathological conditions are known. Theoretically, based on the total number of structural genes of the order of 50-100 thousand, one could assume that most of the pathological mutant alleles have not yet been discovered. Even if we recognize that many of these mutations are lethal, while others, on the contrary, do not affect serious functions and pass clinically unrecognized, then we should expect the continuation of the discovery of more and more forms of hereditary pathology. But we can say with confidence that the most common and giving a clear clinical picture of the disease have already been described. The newly discovered forms are the result of rare mutations. In addition, from a genetic point of view, mutations of the same gene will result, but affecting its new structures or that are different in their molecular nature (for example, mutations in the regulatory rather than structural part of the gene). That is why the discovery of new mutant alleles, the splitting of known diseases into genetically different forms are inseparable from the connection of new genetic approaches to the traditional clinical and genetic analysis, which make it possible to arrive at more discrete and approaching elementary traits.

The first place is occupied by biochemical methods. For the first time, the biochemical approach was applied and proved to be very fruitful at the beginning of this century in the clinical and genetic study of alcaptunuria. It was as a result of this study that a biochemical mendelian trait was found for one of the hereditary diseases, in the form of excessive excretion of homogentisic acid in the urine, and it was suggested that there are similar congenital metabolic diseases with their own specific biochemical defect. Currently, more than 300 hereditary metabolic diseases with the studied anomaly are described in biochemical genetics. In clinical practice, for the biochemical diagnosis of known metabolic diseases, a system of qualitative and semi-quantitative tests is used, with the help of which it is possible to catch the disturbed content of metabolic products (for example, excessive urinary excretion of phenylpyruvic acid in phenylketonuria or homocistin in homocystinuria). The use of various types of electrophoresis and chromatography separately and in combination, as well as other methods, makes it possible to establish which metabolic link is disturbed. To find out which enzyme or other protein is involved in the metabolic effect and what is the change in the protein, as a rule, not only biological fluids, but also the patient's cells are used, complex methods are used to determine the content of the enzyme, its catalytic activity and molecular structure.

Molecular genetic methods, which are of independent importance for deciphering the nature of mutations directly in DNA, are adjacent to biochemical methods. Traditionally, their use is possible after the detection of a defect in the corresponding gene product, but so far it is realistic for a few cases of pathology, for example, for mutations of globin genes.

The fruitfulness of biochemical research methods is largely due to the fact that the biochemical analysis of biological fluids is supplemented by the analysis of body cells. Genetic biochemical analysis on cells turned out to be decisive in the transition to biochemical diagnostics with the analysis of metabolites for the study of enzymes and structural proteins, in particular, cellular receptors.

This led to the discovery of primary defects in protein molecules and many hereditary diseases. Immunological methods are close to biochemical methods in their capabilities. The methods for assessing the level of serum immunoglobulins of different classes, as well as the state of cellular immunity, are used to diagnose and in-depth study of the genetic forms of various hereditary immunodeficiency states. A prominent place in the arsenal of these methods is occupied by classical serological reactions with erythrocytes or leukocytes to determine the state of surface antigens. In recent years, radioimmunochemical methods for determining the defect of hormones and some other biologically active substances have become more and more widely used.

All of these methods are used to identify biochemical defects and the molecular nature of mutations using a population-geographical approach. The significance of this approach lies in the fact that rare defects and mutations can occur mainly in some specific geographic regions in connection with the specific conditions of the human environment. Suffice it to recall the predominant distribution of various genoglobinopathies, especially in the areas of malaria. Isolated populations with a large number of consanguineous marriages often served as a source of the discovery of new mutations due to the more frequent cleavage of homozygotes in a recessive state. The population-geographic approach also helps to differentiate phenotypically similar, but genetically different mutations in large samples of patients.