Mutations disrupting neuritogenesis genes confer risk for cerebral palsy,Nature Genetics

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Mutations disrupting neuritogenesis genes confer risk for cerebral palsy
Nature Genetics ( IF 30.8 ) Pub Date : 2020-09-28 , DOI: 10.1038/s41588-020-0695-1
Sheng Chih Jin _{1,

2,

3} , Sara A Lewis _{4,

5} , Somayeh Bakhtiari _{4,

5} , Xue Zeng _{1,

2} , Michael C Sierant _{1,

2} , Sheetal Shetty _{4,

5} , Sandra M Nordlie _{4,

5} , Aureliane Elie _{4,

5} , Mark A Corbett ₆ , Bethany Y Norton _{4,

5} , Clare L van Eyk ₆ , Shozeb Haider ₇ , Brandon S Guida _{4,

5} , Helen Magee _{4,

5} , James Liu _{4,

5} , Stephen Pastore ₈ , John B Vincent ₈ , Janice Brunstrom-Hernandez ₉ , Antigone Papavasileiou ₁₀ , Michael C Fahey ₁₁ , Jesia G Berry ₆ , Kelly Harper ₆ , Chongchen Zhou ₁₂ , Junhui Zhang ₁ , Boyang Li ₁₃ , Hongyu Zhao ₁₃ , Jennifer Heim ₄ , Dani L Webber ₆ , Mahalia S B Frank ₆ , Lei Xia ₁₄ , Yiran Xu ₁₄ , Dengna Zhu ₁₄ , Bohao Zhang ₁₄ , Amar H Sheth ₁ , James R Knight ₁₅ , Christopher Castaldi ₁₅ , Irina R Tikhonova ₁₅ , Francesc López-Giráldez ₁₅ , Boris Keren ₁₆ , Sandra Whalen ₁₇ , Julien Buratti ₁₆ , Diane Doummar ₁₈ , Megan Cho ₁₉ , Kyle Retterer ₁₉ , Francisca Millan ₁₉ , Yangong Wang ₂₀ , Jeff L Waugh ₂₁ , Lance Rodan ₂₂ , Julie S Cohen ₂₃ , Ali Fatemi ₂₃ , Angela E Lin ₂₄ , John P Phillips ₂₅ , Timothy Feyma ₂₆ , Suzanna C MacLennan ₂₇ , Spencer Vaughan ₂₈ , Kylie E Crompton ₂₉ , Susan M Reid ₂₉ , Dinah S Reddihough ₂₉ , Qing Shang ₁₂ , Chao Gao ₃₀ , Iona Novak ₃₁ , Nadia Badawi ₃₁ , Yana A Wilson ₃₁ , Sarah J McIntyre ₃₁ , Shrikant M Mane ₁₅ , Xiaoyang Wang _{14,

32} , David J Amor ₂₉ , Daniela C Zarnescu ₂₈ , Qiongshi Lu ₃₃ , Qinghe Xing ₂₀ , Changlian Zhu _{14,

32} , Kaya Bilguvar _{1,

15} , Sergio Padilla-Lopez _{4,

5} , Richard P Lifton _{1,

2} , Jozef Gecz ₆ , Alastair H MacLennan ₆ , Michael C Kruer _{4,

5}

Affiliation

Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Laboratory of Human Genetics and Genomics, Rockefeller University, New York, NY, USA.
Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.
Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA.
Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA.
Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.
Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, London, UK.
Molecular Brain Sciences, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
One CP Place, Plano, TX, USA.
Division of Paediatric Neurology, Iaso Children's Hospital, Athens, Greece.
Department of Pediatrics, Monash University, Melbourne, Victoria, Australia.
Henan Key Laboratory of Child Genetics and Metabolism, Rehabilitation Department, Children's Hospital of Zhengzhou University, Zhengzhou, China.
Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Yale Center for Genome Analysis, Yale University, New Haven, CT, USA.
Department of Genetics, Pitié-Salpêtrière Hospital, APHP.Sorbonne Université, Paris, France.
UF de Génétique Clinique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, APHP.Sorbonne Université, Hôpital Armand Trousseau, Paris, France.
Sorbonne Université, APHP, Service de Neurologie Pédiatrique et Centre de Référence Neurogénétique, Hôpital Armand Trousseau, Paris, France.
GeneDx, Gaithersburg, MD, USA.
Institute of Biomedical Science and Children's Hospital, and Key Laboratory of Reproduction Regulation of the National Population and Family Planning Commission (NPFPC), Shanghai Institute of Planned Parenthood Research (SIPPR), IRD, Fudan University, Shanghai, China.
Departments of Pediatrics & Neurology, University of Texas Southwestern and Children's Medical Center of Dallas, Dallas, TX, USA.
Departments of Genetics & Genomics and Neurology, Boston Children's Hospital, Boston, MA, USA.
Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD, USA.
Medical Genetics, Department of Pediatrics, MassGeneral Hospital for Children, Boston, MA, USA.
Departments of Pediatrics and Neurology, University of New Mexico, Albuquerque, NM, USA.
Division of Pediatric Neurology, Gillette Children's Hospital, St Paul, MN, USA.
Department of Paediatric Neurology, Women's & Children's Hospital, Adelaide, South Australia, Australia.
Departments of Molecular & Cellular Biology and Neuroscience, University of Arizona, Tucson, AZ, USA.
Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Melbourne, Victoria, Australia.
Rehabilitation Department, Children's Hospital of Zhengzhou University/Henan Children's Hospital, Zhengzhou, China.
Cerebral Palsy Alliance Research Institute, University of Sydney, Sydney, New South Wales, Australia.
Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA.

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.

中文翻译：

破坏神经发生基因的突变会增加脑瘫的风险

除了通常相关的环境因素外，基因组因素也可能导致脑瘫。我们对 250 个亲子三重奏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富集。八个基因有多个破坏性的从头突变；其中，两个（TUBA1A和CTNNB1）符合全基因组显着性。我们确定了两种新的单基因病因，FBXO31和RHOB，并表明RHOB突变增强了活性状态 Rho 效应子结合，而FBXO31突变降低细胞周期蛋白 D 水平。候选脑瘫风险基因与神经发育障碍基因重叠。网络分析确定了 Rho GTP 酶、细胞外基质、粘着斑和细胞骨架通路的富集。在果蝇反向遗传学筛选中，富集通路中的脑瘫风险基因显示可调节神经运动功能。我们估计 14% 的病例可归因于过多的破坏性新发或隐性变异。这些发现为脑瘫早期神经元连接的遗传介导失调提供了证据。

更新日期：2020-09-28

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