Molecular-genetic characteristics of group of patients with mutations in genes of phosphorylase kinase complex

Glycogen storage diseases (GSD) are a heterogeneous group of inherited defects of metabolism of glycogen. GSD du to phosphorylase kinase (PhK) deficiency named GSD IX is the most common of them. It belongs to liver GSDs and occurs in several subtypes that differ in mode of inheritance and tissue-specificity. PhK consists of several subunits coding by different genes. The genes PHKA2, PHKB and PHKG2 make the main contribution to GSD IX etiology. The aim of this study is analysis of genetic specify and genotype-phenotype correlations in patients with mutations in genes of PhK complex. 36 children with liver pathology from 30 unrelated families were studied. Using massively parallel sequencing technology 47 target genes with mutations resulted in liver pathology were analyzed in patients. In 28 patients 18 different hemizygous mutant alleles of PHKA2 were found. In 4 patients 5 homozygous or compound-heterozygous mutations of PHKG2 were detected. 14 PHKA2 variants and 3 PHKG2 variantss are novel. Heterozygous mutations of PHKB and PHKG2 were found in 3 and 1 pts respectively. Clinical significance of some variants in PHKA2, PHKB and PHKG2 is unclear. Most of detected mutations are missense-mutations. There are a few unclear cases with unreliable missense variants and variants in heterozygous state combined with ambiguous clinical features. The analysis of determined novel mutations and its possible effects on PhK complex shows that the finding of a rare variant is not ample for the diagnosis. Diagnosis confirmation must be based on complex study of all available data of frequencies, homology, gene structure and enzyme activity and combine analysis of genetic, clinical and laboratory features and signs.

гликогеноз, фосфорилазкиназа, PHKA2, PHKB, PHKG2, массовое параллельное секвенирование, glycogen storage disease, phosphorylase kinase, PHKA2, PHKB, PHKG2, massively parallel sequencing

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