Клетки гетерозигот

В чем состоит специфическая функция мутантного гена? Когда мы исследовали в культуре фибробласты кожи и циркулирующие клетки крови от больных, гомозиготных по признаку семейной гиперхолестеролемии, то оказалось, что у них либо вообще нет функционально активных рецепторов ЛНП, либо число таких рецепторов очень мало и клетки не могут с необходимой эффективностью связывать, захватывать и разрушать ЛНП. Другими словами, дефектный ген кодирует аномальный белок рецептора ЛНП. У гомозигот, унаследовавших две дефектные копии гена, невозможен синтез нормальных рецепторов. Клетки же гетерозигот имеют одну копию мутантного гена рецепторов ЛНП и одну нормальную, так что они синтезируют половину нормального количества полноценных рецепторов и могут, следовательно, связывать, поглощать и подвергать деградации ЛНП, но со скоростью вдвое ниже нормы.

Хотя у всех изученных к настоящему времени больных семейной гиперхолестеролемией обнаружены мутации в гене, кодирующем рецептор ЛНП, изменения не всегда одни и те же. В зависимости от того, в каком именно участке гена произошла мутация, рецепторы ЛНП или вообще не будут синтезироваться, или окажутся дефектными, например неспособными к переносу на поверхность клеток, к связыванию ЛНП либо к перемещению в область окаймленной поры.

Результаты исследований, проведенных с радиоактивно меченными ЛНП, показали, что время жизни ЛНП в системе кровообращения у людей, гомозиготных по признаку семейной гиперхолестеролемии, в 2,5 раза больше, чем у здоровых людей с нормальными генами рецепторов ЛНП. (В конце концов и у больных ЛНП удаляются из кровяного русла, но иным, значительно менее эффективным путем.) Обусловленная отсутствием рецепторов низкая скорость удаления и деградации ЛНП — одна из главных причин чрезвычайно высокого уровня ЛНП в крови больных семейной гиперхолестеролемией. Но эта причина не единственная.

 

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