open access publication

Preprint, 2023

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

medRxiv, Page 2023.03.01.23286475, 10.1101/2023.03.01.23286475

Contributors

Calame, Daniel G 0000-0001-6860-372X [1] [2] Guo, Tianyu [3] Wang, Chen [3] Garrett, Lillian 0000-0003-4880-7076 [4] Jolly, Angad 0000-0002-5663-1157 [2] Dawood, Moez 0000-0003-0192-1277 [2] Kurolap, Alina 0000-0002-7005-3621 [5] Henig, Noa Zunz [5] Fatih, Jawid M 0000-0002-3927-2711 [2] Herman, Isabella [1] [2] [6] Du, Haowei [2] Mitani, Tadahiro [2] Becker, Lore 0000-0002-6890-4984 [4] Rathkolb, Birgit 0000-0003-1239-0547 [4] [7] [8] Gerlini, Raffaele 0000-0003-0852-5621 [4] Seisenberger, Claudia [4] Marschal, Susan [9] Hunter, Jill Vanessa [1] [2] Gerard, Amanda E [1] [2] Heidlebaugh, Alexis R [9] Challman, Thomas D 0000-0002-2906-0635 [9] Spillmann, Rebecca C. [10] [11] Jhangiani, Shalini N [2] Coban-Akdemir, Zeynep Hande [2] [12] Lalani, Seema R 0000-0003-0707-657X [1] [2] Liu, Lingxiao [3] Revah-Politi, Anya [13] Iglesias, Alejandro [13] Guzman, Edwin [13] Baugh, Evan [13] Boddaert, Nathalie 0000-0003-0991-7774 [14] Rondeau, Sophie [14] [15] Clothide, Ormieres [14] [15] Barcia, Giulia 0000-0001-6657-5040 [14] [15] Tan, Queenie K.G. [10] [11] Thiffault, Isabelle It [16] Pastinen, Tomi M [16] [17] Sheikh, Kazim A [12] Biliciler, Suur [12] Mei, Davide 0000-0001-6790-6251 [18] [19] Melani, Federico [18] [19] Shashi, Vandana [10] [11] Yaron, Yuval 0000-0001-8622-7668 [5] [20] Steele, Mary [21] Wakeling, Emma L 0000-0001-5712-0044 [22] Østergaard, Elsebet 0000-0002-8047-063X [23] [24] Nazaryan-Petersen, Lusine 0000-0002-4807-6827 [24] Diseases, Network Undiagnosed [2] Millan, Francisca [25] Santiago-Sim, Teresa [25] Thevenon, Julien 0000-0001-9271-3961 [26] Bruel, Ange-Line [26] [27] Thauvin-Robinet, Christel [26] [27] Popp, Denny 0000-0001-5656-2027 [28] Platzer, Konrad 0000-0001-6127-6308 [28] Gawlinski, Pawel 0000-0002-3672-5834 [29] Wiszniewski, Wojciech Krzysztof [30] Marafi, Dana 0000-0003-2233-3423 [2] [31] Pehlivan, Davut 0000-0001-5788-0270 [1] [2] Posey, Jennifer Ellen 0000-0003-4814-6765 [2] Gibbs, Richard A [2] Gailus-Durner, Valerie [4] Guerrini, Renzo 0000-0002-7272-7079 [18] [19] Fuchs, Helmut [4] De Angelis, Martin Hrabé 0000-0002-7898-2353 [4] [8] [32] Hölter, Sabine Maria 0000-0003-4878-5241 [4] [32] Cheung, Hoi-Hung 0000-0001-7178-9289 [3] Gu, Shen 0000-0003-3107-1218 (Corresponding author) [3] Lupski, James R 0000-0001-9907-9246 (Corresponding author) [1] [2]

Affiliations

  1. [1] Texas Children's Hospital
    2. [NORA names: United States; America, North; OECD];
  2. [2] Baylor College of Medicine
    3. [NORA names: United States; America, North; OECD];
  3. [3] Chinese University of Hong Kong
    4. [NORA names: China; Asia, East];
  4. [4] Helmholtz Zentrum München
    5. [NORA names: Germany; Europe, EU; OECD];
  5. [5] Tel Aviv Sourasky Medical Center
    6. [NORA names: Israel; Asia, Middle East; OECD];

Abstract

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 without disease trait associations. Using exome sequencing and family-based rare variant analysis, 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 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 restricted to the nucleus, NLS missense variants abnormally accumulated in the cytoplasm. Fibroblasts from a patient 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 impact DHX9 localization but instead increased R-loop levels and double-stranded DNA breaks. Dhx9 -/-mice exhibit hypoactivity in novel environments, tremor, and sensorineural hearing loss. Taken together, these results establish DHX9 as a critical regulator of mammalian neurodevelopment and neuronal homeostasis.

Keywords

CMT2, Charcot-Marie-Tooth, Charcot-Marie-Tooth disease, DExD/H-box RNA helicases, DExH-box, DHX9, DNA breaks, LOF, LoF variants, NLS, R-loop levels, R-loops, RNA helicase, accumulation, alleles, analysis, associated with cellular stress, association, axonal Charcot-Marie-Tooth disease, breaks, cancer, cell lines, cellular phenotypes, cellular stress, constraints, correlation, cytoplasm, disease, disorders, double-stranded DNA breaks, environment, exome, exome sequencing, family, family-based rare variant analyses, fibroblasts, gene family, genes, genotype-phenotype correlation, hearing loss, helicase, helicase gene, heterozygous missense, homeostasis, homologous recombination, human cell lines, human helicase genes, hypoactivity, increased R-loop levels, individuals, levels, lines, localization, loss, loss-of-function, mammalian neurodevelopment, missense, missense variants, monoallelic variations, mutational constraints, neurodevelopment, neurodevelopment disorders, neurodevelopmental disorder phenotypes, neurodevelopmental disorders, neuronal homeostasis, novel environment, nuclear localization signal (NLS, nucleus, paralogous gene families, paralogs, pathogenic variation, patients, phenomenon, phenotype, rare variant analysis, recombination, regulate transcription, regulation, results, sensorineural hearing loss, sequence, severe neurodevelopmental disorder, stress, trait associations, traits, transcription, tremor, ultra-rare, variant alleles, variant analysis, variants, variation

Funders

  • Muscular Dystrophy Association
  • National Institute of Neurological Disorders and Stroke
  • International Rett syndrome Foundation
  • National Heart Lung and Blood Institute
  • National Human Genome Research Institute
  • Department of Health and Social Care
  • Ministère des Solidarités et de la Santé
  • Uehara Memorial Foundation
  • National Natural Science Foundation of China
  • National Institute for Health and Care Research
  • National Institute of General Medical Sciences
  • Wellcome Trust
  • University Grants Committee

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