Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.
Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.
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DOI：
10.1038/s41588-020-0695-1
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发表时间：
2020-10
期刊：
影响因子：
30.8
通讯作者：
Kruer, Michael C.
中科院分区：
文献类型：
--
作者：
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;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.;Lopez-Giraldez, 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.
除了常见的相关环境因素外，基因组因素也可能导致脑性瘫痪。我们对250个亲子三人组进行了全外显子组测序，并观察到脑瘫病例中破坏性新生突变的丰富。8个基因具有多重破坏性从头突变；其中2个基因(TUBA1A和CTNNB1)具有全基因组意义。我们确定了两个新的单基因病因，FBXO31和RHOB，并表明RHOB突变增强了活性状态Rho效应器的结合，而FBXO31突变降低了细胞周期蛋白D的水平。候选脑瘫风险基因与神经发育障碍基因重叠。网络分析证实Rho GTP酶、细胞外基质、局灶性黏附和细胞骨架途径丰富。在果蝇反向遗传学筛查中，丰富的通路中的脑瘫风险基因被证明调节神经运动功能。我们估计，14%的病例可以归因于过多的破坏性新生或隐性变异。这些发现为脑性瘫痪患者早期神经元连接的基因调节失调提供了证据。
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 (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation 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 Drosophila reverse 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.
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影响因子：
4.2
作者：
Englander, Zoe A.;Sun, Jessica;Case, Laura;Mikati, Mohamad A.;Kurtzberg, Joanne;Song, Allen W.
通讯作者：
Song, Allen W.
影响因子：
14.9
作者：
Fang H;Gough J
通讯作者：
Gough J
影响因子：
1.9
作者：
Costeff, H
通讯作者：
Costeff, H
影响因子：
37.3
作者：
Della Corte CM;Viscardi G;Di Liello R;Fasano M;Martinelli E;Troiani T;Ciardiello F;Morgillo F
通讯作者：
Morgillo F
影响因子：
4.6
作者：
Al-Mubarak B;Abouelhoda M;Omar A;AlDhalaan H;Aldosari M;Nester M;Alshamrani HA;El-Kalioby M;Goljan E;Albar R;Subhani S;Tahir A;Asfahani S;Eskandrani A;Almusaiab A;Magrashi A;Shinwari J;Monies D;Al Tassan N
通讯作者：
Al Tassan N