Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, pathogenic variation causes neurodevelopmental disorder (NDD) traits and cancer. DHX9 encodes a BRCA1-interacting nuclear helicase regulating transcription, R-loops, and homologous recombination and exhibits the highest mutational constraint of all DDX/DHX paralogs but remains unassociated with disease traits in OMIM. Using exome sequencing and family-based rare-variant analyses, we identified 20 individuals with de novo, ultra-rare, heterozygous missense or loss-of-function (LoF) DHX9 variant alleles. Phenotypes ranged from NDDs to the distal symmetric polyneuropathy axonal Charcot-Marie-Tooth disease (CMT2). Quantitative Human Phenotype Ontology (HPO) analysis demonstrated genotype-phenotype correlations with LoF variants causing mild NDD phenotypes and nuclear localization signal (NLS) missense variants causing severe NDD. We investigated DHX9 variant-associated cellular phenotypes in human cell lines. Whereas wild-type DHX9 was restricted to the nucleus, NLS missense variants abnormally accumulated in the cytoplasm. Fibroblasts from an individual with an NLS variant also showed abnormal cytoplasmic DHX9 accumulation. CMT2-associated missense variants caused aberrant nucleolar DHX9 accumulation, a phenomenon previously associated with cellular stress. Two NDD-associated variants, p.Gly411Glu and p.Arg761Gln, altered DHX9 ATPase activity. The severe NDD-associated variant p.Arg141Gln did not affect DHX9 localization but instead increased R-loop levels and double-stranded DNA breaks. Dhx9−/− mice exhibited hypoactivity in novel environments, tremor, and sensorineural hearing loss. All together, these results establish DHX9 as a critical regulator of mammalian neurodevelopment and neuronal homeostasis.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | American Journal of Human Genetics |
| Vol/bind | 110 |
| Udgave nummer | 8 |
| Sider (fra-til) | 1394-1413 |
| Antal sider | 20 |
| ISSN | 0002-9297 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
This study was supported in part by the US National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHBLI) via the Baylor-Hopkins Center for Mendelian Genomics (BHCMG; grant UM1 HG006542 to J.R.L), by the NHGRI via the GREGoR Consortium (grant U01 HG011758 to J.E.P., J.R.L., and R.A.G.) and the Baylor College of Medicine Human Genome Sequencing Center (grant U54HG003273 to R.A.G.), by the US National Institute of Neurological Disorders and Stroke (NINDS; grant R35NS105078 to J.R.L), by the Muscular Dystrophy Association (MDA; grant 512848 to J.R.L.), and by Spastic Paraplegia Foundation Research (grant to J.R.L.). This study was also supported by the General Research Fund of the Research Grants Council of Hong Kong (grants 24101921 to S.G. and 14104321 to H.H.C.) and the National Natural Science Foundation of China (grant 82202045 to S.G.). D.M. was supported by a Medical Genetics Research Fellowship Program through the US National Institutes of Health (NIH; grant T32 GM007526-42 ). T.M. was supported by the Uehara Memorial Foundation . D.P. was supported by a NINDS grant ( 1K23 NS125126-01A1 ) and a Rett Syndrome Research Trust fellowship award from the International Rett Syndrome Foundation (grant 3701-1 ). J.E.P. was supported by NHGRI K08 HG008986 . D.G.C. was supported by an NIH Brain Disorders and Development Training Grant ( T32 NS043124 ), the NIH Medical Genetics Research Fellowship Program (grant T32 GM007526 ), a Chao Physician Scientist Award, and an MDA Development Grant ( 873841 ). Additional acknowledgments can be found within the supplemental information . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2023 American Society of Human Genetics
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