medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLC10.25557/2073-7998.2018.09.13-20medgen-580Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHПоиск и классификация генетических вариантов в генах фосфорилазкиназного комплекса у группы пациентов с подозрением на наследственные нарушения метаболизма гликогенаMolecular-genetic characteristics of group of patients with mutations in genes of phosphorylase kinase complexКаменецЕ. А.KamenetsE. A.elenakamenec@yandex.ruСтроковаТ. В.StrokovaT. V.noemail@neicon.ruБагаеваМ. Э.BagaevaM. E.noemail@neicon.ruЗубовичА. И.ZubovichA. I.noemail@neicon.ruМеликянМ. А.MelikyanM. A.noemail@neicon.ruГусароваЕ. А.GusarovaE. A.noemail@neicon.ruМиловановаН. В.MilovanovaN. V.noemail@neicon.ruЗахароваЕ. Ю.ZakharovaE. Y.noemail@neicon.ruФГБНУ «Медико-генетический научный центр»РоссияFederal State Budgetary Institution «Research Centre for Medical GeneticsRussian FederationФГБУН «Федеральный исследовательский центр питания и биотехнологии»; Российский национальный исследовательский медицинский университет имени Н.И. ПироговаРоссияFederal State Budgetary Institution «Federal Research Centre for Nutrition and Biotechnology»; Pirogov Russian National Research Medical UniversityRussian FederationФГБУН «Федеральный исследовательский центр питания и биотехнологии»РоссияFederal State Budgetary Institution «Federal Research Centre for Nutrition and Biotechnology»Russian FederationФГБУ «Национальный медицинский исследовательский центр эндокринологии»РоссияFederal State Budgetary Institution «National Research Centre for Endocrinology»Russian Federation2018010920181791320Copyright © Каменец Е.А., Строкова Т.В., Багаева М.Э., Зубович А.И., Меликян М.А., Гусарова Е.А., Милованова Н.В., Захарова Е.Ю., 20182018Каменец Е.А., Строкова Т.В., Багаева М.Э., Зубович А.И., Меликян М.А., Гусарова Е.А., Милованова Н.В., Захарова Е.Ю.Kamenets E.A., Strokova T.V., Bagaeva M.E., Zubovich A.I., Melikyan M.A., Gusarova E.A., Milovanova N.V., Zakharova E.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medgen-journal.ru/jour/article/view/580

Гликогеновые болезни (ГБ) - это гетерогенная группа наследственных нарушений метаболизма гликогена, наиболее распространенным из которых является ГБ IX типа - дефект фермента фосфорилазкиназы (Фк). ГБ IX типа относится к печеночным формам ГБ и подразделяется на несколько подтипов, которые различаются по типу наследования и вовлечению печеночной и мышечной тканей. Фк состоит из нескольких субъединиц, кодируемых различными генами. Наиболее частыми являются подтипы ГБ IX, ассоциированные с мутациями генов PHKA2, PHKB и PHKG2 . Целью данного исследования является анализ генетических особенностей и гено-фенотипических корреляций у пациентов с мутациями в генах комплекса Фк. В исследование включены 36 пациентов из 30 неродственных семей. Методом массового параллельного секвенированияу пациентов были исследованы 47 таргетных генов, ответственных за наследственные болезни, протекающие с поражением печени. У 28 пациентов выявлено 18 различных вариантов в гене PHKA2 в гемизиготном состоянии, у 4 пациентов - 5 различных аллелей в гене PHKG2 в гомозиготном и компаунд-гетерозиготном состоянии . 14 вариантов в гене PHKA2 и 3 в гене PHKG2 ранее не описаны. Гетерозиготные варианы в генах PHKB и PHKG2 выявлены у 3 и 1 пациента соответственно. Клиническое значение некоторых вариантов в генах PHKA2, PHKB и PHKG2 неоднозначно. Большинство изменений составили миссенс-замены. Имеется несколько сомнительных случаев с миссенс-заменами неясного значения, либо гетерозиготными изменениями и неоднозначными клиническими симптомами. Показано, что обнаружение редкого варианта не всегда является основанием для верификации диагноза. Для его подтверждения необходимо комплексное изучение всей доступной информации о встречаемости, гомологии, структуре гена и активности фермента, сводный анализ генетических, клинических и лабораторных данных.

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.

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The authors declare that there are no conflicts of interest present.