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在PRPF8,DYRK2和CEP78中的CAKUT变异:对剪接和纤维生成的影响

Lea M Merz^1,2, Shirlee Shril¹, Tucker J Carrocci³

¹Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

bioRxiv : the preprint server for biology

|August 8, 2025

概括

在PRPF8和EDD-DYRK2-DDB1复合体中的遗传变异与脏和泌尿道 (CAKUT) 的先天性异常有关. 这些发现揭示了新的疾病机制,包括受损的拼接和纤毛发育.

科学领域:

遗传学遗传学是一个
分子生物学分子生物学
发展生物学发展生物学

背景情况:

脏和尿路的先天性异常 (CAKUT) 是儿童慢性病的主要原因.
已知CAKUT的50多个单一原因,但许多遗传基础仍未确定.
PRPF8,一个spliceosome组件,对于mRNA前拼接和纤维生成至关重要.

研究的目的:

为了识别CAKUT的新型遗传原因.
调查PRPF8和EDD-DYRK2-DDB1复合体中发现的变异的功能影响.
为了阐明CAKUT病原体的基础分子机制.

主要方法:

在208个CAKUT家族中进行了三元外基因组测序.
功能验证包括酵母拼接测试,RPE-1细胞中的Sonic刺信号测试,共免疫沉和鼠标胚胎在现场杂交.
使用AlphaFold进行了蛋白质相互作用建模.

主要成果:

在CAKUT患者中发现了PRPF8,DYRK2,DDB1,EDD和CEP78的异合体变异.
一种de novo的PRPF8变种损害了非共识拼接点的拼接,并导致酵母无活性.
变种影响了拼接,SHH信号,蛋白质复合体形成,并在发育中的小鼠脏中显示了特定的表达模式.

结论:

在PRPF8和EDD-DYRK2-DDB1复合体的变体通过损坏的拼接和纤毛发育有助于CAKUT.
这项研究揭示了CAKUT和纤毛病的候选基因的新型功能网络.
这些发现为疾病机制和脏发育障碍的潜在治疗标提供了新的见解.

关键词:

脏和尿道的先天性异常 (CAKUT)纤维细胞的产生.纤维病变 (ciliopathy) 是一种纤维病变.外基因组测序是指外基因组的测序.脏的发育脏的发育拼接拼接拼接拼接

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