학술논문
Mutations disrupting neuritogenesis genes confer risk for cerebral palsy
Document Type
Article
Author
Jin, Sheng Chih; Lewis, Sara A.; Bakhtiari, Somayeh; Zeng, Xue; Sierant, Michael C.; Shetty, Sheetal; Nordlie, Sandra M.; Elie, Aureliane; Corbett, Mark A.; Norton, Bethany Y.; van Eyk, Clare L.; Haider, Shozeb; Guida, Brandon S.; Magee, Helen; Liu, James; Pastore, Stephen; Vincent, John B.; Brunstrom-Hernandez, Janice; Papavasileiou, Antigone; Fahey, Michael C.; Berry, Jesia G.; Harper, Kelly; Zhou, Chongchen; Zhang, Junhui; Li, Boyang; Zhao, Hongyu; Heim, Jennifer; Webber, Dani L.; Frank, Mahalia S. B.; Xia, Lei; Xu, Yiran; Zhu, Dengna; Zhang, Bohao; Sheth, Amar H.; Knight, James R.; Castaldi, Christopher; Tikhonova, Irina R.; López-Giráldez, Francesc; Keren, Boris; Whalen, Sandra; Buratti, Julien; Doummar, Diane; Cho, Megan; Retterer, Kyle; Millan, Francisca; Wang, Yangong; Waugh, Jeff L.; Rodan, Lance; Cohen, Julie S.; Fatemi, Ali; Lin, Angela E.; Phillips, John P.; Feyma, Timothy; MacLennan, Suzanna C.; Vaughan, Spencer; Crompton, Kylie E.; Reid, Susan M.; Reddihough, Dinah S.; Shang, Qing; Gao, Chao; Novak, Iona; Badawi, Nadia; Wilson, Yana A.; McIntyre, Sarah J.; Mane, Shrikant M.; Wang, Xiaoyang; Amor, David J.; Zarnescu, Daniela C.; Lu, Qiongshi; Xing, Qinghe; Zhu, Changlian; Bilguvar, Kaya; Padilla-Lopez, Sergio; Lifton, Richard P.; Gecz, Jozef; MacLennan, Alastair H.; Kruer, Michael C.
Source
Nature Genetics; October 2020, Vol. 52 Issue: 10 p1046-1056, 11p
Subject
Language
ISSN
10614036; 15461718
Abstract
In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent–offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1Aand CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31and RHOB, and showed that the RHOBmutation enhances active-state Rho effector binding while the FBXO31mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophilareverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.