möglich sobald bei der ZB eingereicht worden ist.
Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease.
Am. J. Hum. Genet. 110, 1394-1413 (2023)
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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Charcot-marie-tooth Disease ; Dexd/h-box Rna Helicases ; Dhx9 ; Dna Damage Repair ; R-loops ; Allelic Series ; Epilepsy ; Homologous Recombination ; Neurodevelopmental Disorders ; Neuropathy; Copy-number Variation; Rna Helicase; Intellectual Disability; Spinocerebellar Ataxia; Common-cause; Mutation; Phenotype; Ddx3x; Identification; Transcription
ISSN (print) / ISBN
0002-9297
e-ISSN
1537-6605
Zeitschrift
American Journal of Human Genetics, The
Quellenangaben
Band: 110,
Heft: 8,
Seiten: 1394-1413
Verlag
Elsevier
Verlagsort
New York, NY
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Förderungen
National Heart, Lung, and Blood Institute (NHBLI) via the Baylor-Hopkins Center
NHGRI
Baylor College of Medicine Human Genome Sequencing Center
US National Institute of Neurological Disorders and Stroke (NINDS)
Muscular Dystrophy Association (MDA)
Spastic Paraplegia Foundation Research
General Research Fund of the Research Grants Council of Hong Kong
US National Human Genome Research Institute (NHGRI)
Medical Genetics Research Fellowship Program through the US National Institutes of Health (NIH)
Uehara Memorial Foundation
NINDS grant
Rett Syndrome Research Trust fellowship award from the International Rett Syndrome Foundation
NIH Brain Disorders and Development Training Grant
NIH Medical Genetics Research Fellowship Program
Chao Physician Scientist Award
MDA Development Grant
National Natural Science Foundation of China
NHGRI
Baylor College of Medicine Human Genome Sequencing Center
US National Institute of Neurological Disorders and Stroke (NINDS)
Muscular Dystrophy Association (MDA)
Spastic Paraplegia Foundation Research
General Research Fund of the Research Grants Council of Hong Kong
US National Human Genome Research Institute (NHGRI)
Medical Genetics Research Fellowship Program through the US National Institutes of Health (NIH)
Uehara Memorial Foundation
NINDS grant
Rett Syndrome Research Trust fellowship award from the International Rett Syndrome Foundation
NIH Brain Disorders and Development Training Grant
NIH Medical Genetics Research Fellowship Program
Chao Physician Scientist Award
MDA Development Grant
National Natural Science Foundation of China