Новый вариант c.1185_1196dup (p.(Gly396_Ser399dup)) в гене SLC26A4, ассоциированный с рецессивно наследуемой тугоухостью

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. 

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