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Các đột biến cắt bỏ trong NRXN2 và NRXN1 trong các rối loạn phổ tự kỷ và tâm thần phân liệt
Tóm tắt
Sự gia tăng bằng chứng di truyền đang hội tụ ủng hộ các cơ chế bệnh lý chung cho các rối loạn phổ tự kỷ (ASD), khuyết tật trí tuệ (ID hoặc chậm phát triển trí tuệ) và tâm thần phân liệt (SCZ), ba rối loạn phát triển thần kinh ảnh hưởng đến nhận thức và hành vi. Các biến thể số bản sao và các đột biến có hại trong các protein tổ chức synapse, bao gồm NRXN1, đã được liên kết với các rối loạn phát triển thần kinh này, nhưng chưa phát hiện được các liên kết tương tự đối với NRXN2 hoặc NRXN3. Từ việc tái giải trình tự ba gen neurexin ở những cá nhân bị ảnh hưởng bởi ASD (n = 142), SCZ (n = 143) hoặc ID không hội chứng (n = 94), chúng tôi đã xác định được một đột biến cắt bỏ trong NRXN2 ở một bệnh nhân bị ASD, đột biến này được di truyền từ một người cha mắc chứng chậm phát triển ngôn ngữ nghiêm trọng và có lịch sử gia đình bị SCZ. Chúng tôi cũng đã xác định được một đột biến cắt bỏ de novo trong NRXN1 ở một bệnh nhân bị SCZ, cùng với một số đột biến tiềm năng gây bệnh khác liên quan đến ASD. Các đột biến cắt bỏ này dẫn đến các protein không thể thúc đẩy sự phân biệt synapse trong nuôi cấy đồng tế bào và không có khả năng gắn kết với bất kỳ đối tác gắn kết sau synapse đã được xác định nào, như LRRTM2 hoặc NLGN2 trong các thử nghiệm gắn kết tế bào. Những phát hiện của chúng tôi lần đầu tiên liên kết sự gián đoạn NRXN2 với sinh bệnh học của ASD và củng cố thêm vai trò của NRXN1 trong SCZ, hỗ trợ quan điểm về một cơ chế di truyền chung trong các rối loạn này.
Từ khóa
#rối loạn phổ tự kỷ #tâm thần phân liệt #đột biến cắt bỏ #NRXN1 #NRXN2 #di truyền học #phát triển thần kinhTài liệu tham khảo
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