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Mutations disrupting neuritogenesis genes confer risk for cerebral palsy
Nature genetics, 2020-10, Vol.52 (10), p.1046-1056
2020
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Autor(en) / Beteiligte
Titel
Mutations disrupting neuritogenesis genes confer risk for cerebral palsy
Ist Teil von
  • Nature genetics, 2020-10, Vol.52 (10), p.1046-1056
Ort / Verlag
United States: Nature Publishing Group
Erscheinungsjahr
2020
Quelle
MEDLINE
Beschreibungen/Notizen
  • 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.
Sprache
Englisch
Identifikatoren
ISSN: 1061-4036, 1546-1718
eISSN: 1546-1718
DOI: 10.1038/s41588-020-0695-1
Titel-ID: cdi_pubmed_primary_32989326
Format
–
Schlagworte
alk kinase, Animals, Autism, Axonogenesis, beta Catenin - genetics, Binding sites, brain, Cerebral palsy, Cerebral Palsy - genetics, Cerebral Palsy - pathology, congenital heart-disease, copy-number variations, Cyclin D, Cyclin D - genetics, Cytoskeleton, Cytoskeleton - genetics, de-novo, disability, Drosophila - genetics, Enrichment, Environmental factors, Etiology, Exome - genetics, Exome Sequencing, Extracellular matrix, Extracellular Matrix - genetics, F-Box Proteins - genetics, Female, Focal Adhesions - genetics, Genes, Genetic Predisposition to Disease, Genetics, Genetics & Heredity, Genetik, Genome, Human - genetics, Genomes, Humans, Hypoxia, intellectual, Ischemia, Kinases, Language disorders, Magnetic resonance imaging, Male, Medical Genetics, Medicin och hälsovetenskap, Medicinsk genetik, Movement disorders, Mutation, Mutation - genetics, Neural networks, Neurites - metabolism, Neurites - pathology, Neurodevelopmental disorders, Offspring, Paralysis, phosphorylation, protein, Proteins, rare, rhoB GTP-Binding Protein - genetics, Risk, Risk Factors, Sequence Analysis, DNA, Signal Transduction - genetics, truncating mutations, Tubulin - genetics, Tumor Suppressor Proteins - genetics

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