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  • X-linked monogenic diseases

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    Hemophilia A( 306700, Xq28, F8C gene defects, K recessive) is due to the hereditary defect of factor VIII, the most important component of the coagulating system of blood.

    Factor VIII - anti-hemophilic globulin A - circulates in the blood as a complex of three subunits, designated VIII-k( coagulating unit), VIII-Ar( the main antigen marker) and VIII-PV( von Willebrand factor bound to VIII-Ar).It is believed that VIII-FV regulates the synthesis of the coagulation part of anti-hemophilic globulin( VIII-k).The main complex - VIII-k, is encoded by the F8 gene located in chromosome X.

    Sporadic cases of hemophilia A account for 30%, the remaining 70% fall on family variants. Approximately 10% of all identified mutations in the F8 gene account for deletions, 5% for short deletions and gene duplications, the rest are point mutations.

    Hemophilia B( 306900, Xq27.1-q27.2, defects of F9, HEMB, K, recessive) is due to a hereditary defect of factor IX.The synthesis of factor IX in hepatocytes is encoded by the F9 gene. The F9 gene is characterized by a high incidence of mutations( more than 400 mutations are now identified).The vast majority of them are replacements of nucleotides. In 40% of cases with severe inhibitory forms of hemophilia B, deletions of various lengths are found in patients.

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    To diagnose hemophilia B, direct and indirect molecular genetic methods are used. Indirect diagnosis is based on PCR analysis of intragenic polymorphic sites: Taql( at position 11109-11113);insertion polymorphism( restriction enzymes Hinfl and Ddel).The RFLP-analysis method is informative only in 60-70% of all families with hemophilia B. Direct diagnosis of the disease is carried out using PCR.

    Duchenne's myodystrophy( * 310200, Xp21.2, dystrophin DMD gene, K recessive) - arises as a result of defects in the gene that encodes the protein dystrophin, which is a part of muscular fiber sarcolemma. There are two clinical forms of the disease: severe - Duchenne's myodystrophy and relatively favorable Becker's myodystrophy. In Duchenne miodistrophy, dystrophin is either completely absent or degraded shortly after synthesis. In the Becker form, dystrophin is present in a modified form( most often truncated).

    Various mutations of the DMD gene are known. In 60% of cases, long deletions are found in the DMD gene, 30% of them are located in the proximal part of the gene, 70% in the distal part. There is no direct correlation between the severity of the course of the disease and the extent of the deletion. Often, other DMD mutations are detected: in 5% - duplications, in 35% - point mutations.

    To diagnose deletions in DMD, PCR is most often used.

    For the treatment, methods of gene correction( introducing retro-viral or adenoviral gene constructs containing the fully-differentiated code DNA of the DMD gene) are developed.

    Vitamin D-resistant rickets( familial hypophosphatemic rickets, phosphate diabetes) is a group of hereditary diseases caused by impaired absorption of phosphate in the intestine( X-linked form: type I, 307800, type II # 307810, both types - K dominant, recessive form: 241520, p; dominant form: 193100, ED).The severity of the disease can range from some delay in growth to severe rickets with osteomalacia. Rakhitic changes begin to develop in children at the age of 1-2 years. In the study of blood, a decrease in the phosphate concentration is detected, an increase in the activity of alkaline phosphatase, a concentration of calcium and PTH is usually normal.