X-linked monogenic diseases

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.

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.