vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-26-82vavilov-5235Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSНовый вариант c.1185_1196dup (p.(Gly396_Ser399dup)) в гене SLC26A4, ассоциированный с рецессивно наследуемой тугоухостьюA novel variant c.1185_1196dup (p.(Gly396_Ser399dup)) in the SLC26A4 gene associated with recessive hearing lossЗыцарьМ. В.ZytsarM. V.

Новосибирск

Novosibirsk

zytzar@bionet.nsc.ruДанильченкоВ. Ю.DanilchenkoV. Yu.

Новосибирск

Novosibirsk

БондарьА. А.BondarA. A.

Новосибирск

Novosibirsk

ОрищенкоК. Е.OrishchenkoK. E.

Новосибирск

Novosibirsk

ПосухО. Л.PosukhO. L.

Новосибирск

Novosibirsk

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университетРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State UniversityRussian FederationИнститут химической биологии и фундаментальной медицины им. Д.Г. Кнорре Сибирского отделения Российской академии наукРоссияKnorre Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of SciencesRussian Federation202626082026305814823Copyright © Зыцарь М.В., Данильченко В.Ю., Бондарь А.А., Орищенко К.Е., Посух О.Л., 20262026Зыцарь М.В., Данильченко В.Ю., Бондарь А.А., Орищенко К.Е., Посух О.Л.Zytsar M.V., Danilchenko V.Y., Bondar A.A., Orishchenko K.E., Posukh O.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/5235

Патогенные варианты в гене SLC26A4 (solute carrier family 26, member 4) – частая причина наследственной потери слуха. Ген SLC26A4 кодирует трансмембранный белок пендрин из семейства анионных транспортеров SLC26, с преимущественной экспрессией в тканях внутреннего уха, щитовидной железы и почек.

Патогенные SLC26A4-варианты вызывают несиндромальную рецессивно наследуемую потерю слуха (DFNB4) и синдром Пендреда (сенсоневральная тугоухость и дисфункция щитовидной железы). Во многих исследованиях при анализе гена SLC26A4, наряду с пациентами, у которых обнаружено два рецессивных патогенных SLC26A4варианта (М2-пациенты) и может быть поставлен точный молекулярно-генетический диагноз, часто выявляется группа пациентов только с одним патогенным SLC26A4-вариантом (М1-пациенты), что создает диагностическую проблему. Наличие М1-пациентов может отражать не обнаруженные рутинными методами диагностики вариации числа копий (CNV, делеции/дупликации в гене) SLC26A4. Цель работы – поиск делеций/дупликаций в гене SLC26A4 методом MLPA (Multiplex Ligation-dependent Probe Amplification) у 13 пациентов, относящихся к коренному населению Республики Тыва (Южная Сибирь), у которых при изучении этиологии наследственной потери слуха был найден только один патогенный SLC26A4-вариант (М1-пациенты). В результате MLPA-анализа и молекулярного клонирования в образцах ДНК трех М1-пациентов из двух родственных тувинских семей обнаружен новый вариант – тандемная дупликация 12 нуклеотидов (c.1185_1196dup) в экзоне 10 гена SLC26A4, которая является внутрирамочной инсерцией, приводящей к включению четырех дополнительных аминокислотных остатков Gly-Phe-Phe-Ser (p.(Gly396_Ser399dup)) в высококонсервативном районе белка пендрин. Бóльшая часть предсказательных программ прогнозирует повреждающее воздействие варианта c.1185_1196dup на структуру и функцию белка пендрин. В пользу патогенности свидетельствует его сегрегация с патологией слуха в родословной пациентов, у которых он найден в компаунд-гетерозиготном состоянии с патогенными SLC26A4вариантами, а также его отсутствие в контрольной выборке тувинцев и мировых базах геномных данных. Для подтверждения потенциально негативных эффектов нового варианта c.1185_1196dup (p.(Gly396_Ser399dup)) и его ассоциации с патологией слуха необходимы функциональные in vitro исследования. 

Pathogenic variants in the SLC26A4 gene (solute carrier family 26, member 4) are a common cause of inherited hearing loss. The SLC26A4 gene encodes the transmembrane protein pendrin, a member of the SLC26 anion transporter family, with predominant expression in the inner ear, thyroid, and kidney tissues. Pathogenic SLC26A4 variants cause nonsyndromic recessive hearing loss (DFNB4) and Pendred syndrome (sensorineural hearing loss and thyroid dysfunction). In many studies analyzing the SLC26A4 gene, along with patients who have two recessive pathogenic SLC26A4 variants (M2 patients) and an accurate molecular genetic diagnosis can be made, a group of patients with only one pathogenic SLC26A4 variant (M1 patients) is often identified, which creates a diagnostic problem. The presence of M1 patients may reflect copy number variations (CNVs, deletions/duplications) in the SLC26A4 gene that are not detected by routine diagnostic methods. The aim of the study is to search for deletions/duplications in the SLC26A4 gene using the MLPA (Multiplex Ligation-dependent Probe Amplification) method in thirteen patients belonging to the indigenous people of the Tyva Republic (Southern Siberia), in whom only one pathogenic SLC26A4 variant (M1 patients) was identified during the study of the etiology of hereditary hearing loss. As a result of MLPA analysis and molecular cloning in DNA samples of three M1 patients from two related Tuvinian families, a novel variant was revealed – tandem duplication of twelve nucleotides (c.1185_1196dup) in exon 10 of the SLC26A4 gene. This variant is an in-frame insertion resulting in the inclusion of four additional amino acid residues Gly-Phe-Phe-Ser (p.(Gly396_Ser399dup)) in a highly conserved region of the pendrin protein. Most predictive programs predict the damaging effect of the c.1185_1196dup variant on the structure and function of the pendrin protein. The pathogenicity of the c.1185_1196dup variant is supported by its segregation with hearing pathology in the pedigree of patients in whom it was found in a compound heterozygous state with pathogenic SLC26A4 variants, as well as its absence in a control sample of Tuvinians and in the world genomic databases. Functional in vitro studies are needed to confirm the potentially deleterious effects of the novel c.1185_1196dup (p.(Gly396_Ser399dup)) variant and its association with hearing pathology. 

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