Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease

KIZ OpenIR > 其他

	Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease
	Calame, DG; Guo, TY; Wang, C; Garrett, L; Jolly, A; Dawood, M; Kurolap, A; Henig, NZ; Fatih, JM; Herman, I; Du, HW; Mitani, T; Becker, L; Rathkolb, B; Gerlini, R; Seisenberger, C; Marschall, S; Hunter, J; Gerard, A; Heidlebaugh, A; Challman, T; Spillmann, RC; Jhangiani, SN; Coban-Akdemir, Z; Lalani, S; Liu, LX; Revah-Politi, A; Iglesias, A; Guzman, E; Baugh, E; Boddaert, N; Rondeau, S; Ormieres, C; Barcia, G; Tan, QKG; Thiffault, SI; Pastinen, T; Sheikh, K; Biliciler, S; Mei, D; Melani, F; Shashi, V; Yaron, Y; Steele, M; Wakeling, E; Ostergaard, E; Millan, F; Santiago-Sim, T; Thevenon, J; Bruel, AL; Thauvin-Robinet, C; Popp, D; Platzer, K; Gawlinski, P; Wiszniewski, W; Marafi, D; Pehlivan, D; Posey, JE; Gibbs, RA; Gailus-Durner, V; Guerrini, R; Fuchs, H; de Angelis, MH; Hölter, SM; Cheung, HH; Gu, S; Lupski, JR
	2023
发表期刊	AMERICAN JOURNAL OF HUMAN GENETICS
ISSN	0002-9297
卷号	110 期号:8 页码:1394+
摘要	DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, path-ogenic variation causes neurodevelopmental disorder (NDD) traits and cancer. DHX9 encodes a BRCA1-interacting nuclear helicase regu-lating 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 envi-ronments, tremor, and sensorineural hearing loss. All together, these results establish DHX9 as a critical regulator of mammalian neuro-development and neuronal homeostasis.
收录类别	SCI
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/14112
专题	其他
推荐引用方式 GB/T 7714	Calame, DG,Guo, TY,Wang, C,et al. Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease[J]. AMERICAN JOURNAL OF HUMAN GENETICS,2023,110(8):1394+.
APA	Calame, DG.,Guo, TY.,Wang, C.,Garrett, L.,Jolly, A.,...&Lupski, JR.(2023).Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease.AMERICAN JOURNAL OF HUMAN GENETICS,110(8),1394+.
MLA	Calame, DG,et al."Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease".AMERICAN JOURNAL OF HUMAN GENETICS 110.8(2023):1394+.

条目包含的文件
文件名称/大小	文献类型	版本类型	开放类型	使用许可
2024053114.pdf（4359KB）	期刊论文	出版稿	开放获取	CC BY-NC-SA	请求全文