SUMMARY:
DHX9 is a critical regulator of mammalian neurodevelopment and neuronal homeostasis.
TITLE:
Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease
DESCRIPTION:
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…
CONTENT:
Am J Hum Genet. 2023 Jul 13:S0002-9297(23)00214-8. doi: 10.1016/j.ajhg.2023.06.013. Online ahead of print.
ABSTRACT
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.
PMID:37467750 | DOI:10.1016/j.ajhg.2023.06.013
SOURCE:
American journal of human genetics
TAGS:
DHX9
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2023-07-18T14:32:54Z
DATE – DOI: 2023-07-18T14:32:54Z
DATE – PUBMED: 2023 Jul 13
DATE OUTPUT MATCHED: True
DATE – ADDED:
Wed, 19 Jul 2023 06:00:00 -0400
DATE – RETRIEVED:
07/20/23 01:03AM
2023-07-20T01:03:22-04:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:37467750,doi:10.1016/j.ajhg.2023.06.013
PUBMED ID:
pubmed:37467750
DOI:
10.1016/j.ajhg.2023.06.013
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/37467750/
LINK – DOI:
https://doi.org/10.1016/j.ajhg.2023.06.013
LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S0002929723002148
REFERENCES:
CMT Treatment Report, Urgent Research, 2023-07-20T01:03:22-04:00, https://www.cmttreatmentreport.com.
