Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.

Autor: Jin SC; 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., Lewis SA; 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., Bakhtiari S; 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., Zeng X; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.; Laboratory of Human Genetics and Genomics, Rockefeller University, New York, NY, USA., Sierant MC; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.; Laboratory of Human Genetics and Genomics, Rockefeller University, New York, NY, USA., Shetty S; 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., Nordlie SM; 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., Elie A; 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., Corbett MA; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia., Norton BY; 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., van Eyk CL; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia., Haider S; Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, London, UK., Guida BS; 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., Magee H; 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., Liu J; 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., Pastore S; Molecular Brain Sciences, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada., Vincent JB; Molecular Brain Sciences, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada., Brunstrom-Hernandez J; One CP Place, Plano, TX, USA., Papavasileiou A; Division of Paediatric Neurology, Iaso Children's Hospital, Athens, Greece., Fahey MC; Department of Pediatrics, Monash University, Melbourne, Victoria, Australia., Berry JG; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia., Harper K; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia., Zhou C; Henan Key Laboratory of Child Genetics and Metabolism, Rehabilitation Department, Children's Hospital of Zhengzhou University, Zhengzhou, China., Zhang J; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA., Li B; Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA., Zhao H; Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA., Heim J; Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA., Webber DL; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia., Frank MSB; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia., Xia L; Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Xu Y; Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Zhu D; Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Zhang B; Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Sheth AH; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA., Knight JR; Yale Center for Genome Analysis, Yale University, New Haven, CT, USA., Castaldi C; Yale Center for Genome Analysis, Yale University, New Haven, CT, USA., Tikhonova IR; Yale Center for Genome Analysis, Yale University, New Haven, CT, USA., López-Giráldez F; Yale Center for Genome Analysis, Yale University, New Haven, CT, USA., Keren B; Department of Genetics, Pitié-Salpêtrière Hospital, APHP.Sorbonne Université, Paris, France., Whalen S; UF de Génétique Clinique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, APHP.Sorbonne Université, Hôpital Armand Trousseau, Paris, France., Buratti J; Department of Genetics, Pitié-Salpêtrière Hospital, APHP.Sorbonne Université, Paris, France., Doummar D; Sorbonne Université, APHP, Service de Neurologie Pédiatrique et Centre de Référence Neurogénétique, Hôpital Armand Trousseau, Paris, France., Cho M; GeneDx, Gaithersburg, MD, USA., Retterer K; GeneDx, Gaithersburg, MD, USA., Millan F; GeneDx, Gaithersburg, MD, USA., Wang Y; 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., Waugh JL; Departments of Pediatrics & Neurology, University of Texas Southwestern and Children's Medical Center of Dallas, Dallas, TX, USA., Rodan L; Departments of Genetics & Genomics and Neurology, Boston Children's Hospital, Boston, MA, USA., Cohen JS; Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD, USA., Fatemi A; Division of Neurogenetics and Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD, USA., Lin AE; Medical Genetics, Department of Pediatrics, MassGeneral Hospital for Children, Boston, MA, USA., Phillips JP; Departments of Pediatrics and Neurology, University of New Mexico, Albuquerque, NM, USA., Feyma T; Division of Pediatric Neurology, Gillette Children's Hospital, St Paul, MN, USA., MacLennan SC; Department of Paediatric Neurology, Women's & Children's Hospital, Adelaide, South Australia, Australia., Vaughan S; Departments of Molecular & Cellular Biology and Neuroscience, University of Arizona, Tucson, AZ, USA., Crompton KE; Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Melbourne, Victoria, Australia., Reid SM; Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Melbourne, Victoria, Australia., Reddihough DS; Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Melbourne, Victoria, Australia., Shang Q; Henan Key Laboratory of Child Genetics and Metabolism, Rehabilitation Department, Children's Hospital of Zhengzhou University, Zhengzhou, China., Gao C; Rehabilitation Department, Children's Hospital of Zhengzhou University/Henan Children's Hospital, Zhengzhou, China., Novak I; Cerebral Palsy Alliance Research Institute, University of Sydney, Sydney, New South Wales, Australia., Badawi N; Cerebral Palsy Alliance Research Institute, University of Sydney, Sydney, New South Wales, Australia., Wilson YA; Cerebral Palsy Alliance Research Institute, University of Sydney, Sydney, New South Wales, Australia., McIntyre SJ; Cerebral Palsy Alliance Research Institute, University of Sydney, Sydney, New South Wales, Australia., Mane SM; Yale Center for Genome Analysis, Yale University, New Haven, CT, USA., Wang X; Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden., Amor DJ; Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Melbourne, Victoria, Australia., Zarnescu DC; Departments of Molecular & Cellular Biology and Neuroscience, University of Arizona, Tucson, AZ, USA., Lu Q; Department of Biostatistics & Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA., Xing Q; 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., Zhu C; Henan Key Laboratory of Child Brain Injury, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.; Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden., Bilguvar K; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.; Yale Center for Genome Analysis, Yale University, New Haven, CT, USA., Padilla-Lopez S; 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., Lifton RP; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.; Laboratory of Human Genetics and Genomics, Rockefeller University, New York, NY, USA., Gecz J; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia., MacLennan AH; Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia., Kruer MC; Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA. kruerm@email.arizona.edu.; Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA. kruerm@email.arizona.edu.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2020 Oct; Vol. 52 (10), pp. 1046-1056. Date of Electronic Publication: 2020 Sep 28.
DOI: 10.1038/s41588-020-0695-1
Abstrakt: 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.
Databáze: MEDLINE