Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy
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Published:2022-04-28
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Kim Hong JooORCID, Mohassel PayamORCID, Donkervoort Sandra, Guo Lin, O’Donovan Kevin, Coughlin Maura, Lornage Xaviere, Foulds Nicola, Hammans Simon R., Foley A. Reghan, Fare Charlotte M.ORCID, Ford Alice F., Ogasawara Masashi, Sato Aki, Iida AritoshiORCID, Munot Pinki, Ambegaonkar Gautam, Phadke Rahul, O’Donovan Dominic G., Buchert RebeccaORCID, Grimmel Mona, Töpf Ana, Zaharieva Irina T., Brady Lauren, Hu Ying, Lloyd Thomas E.ORCID, Klein Andrea, Steinlin Maja, Kuster Alice, Mercier Sandra, Marcorelles Pascale, Péréon Yann, Fleurence EmmanuelleORCID, Manzur Adnan, Ennis SarahORCID, Upstill-Goddard RosannaORCID, Bello LucaORCID, Bertolin Cinzia, Pegoraro Elena, Salviati LeonardoORCID, French Courtney E.ORCID, Shatillo AndriyORCID, Raymond F. LucyORCID, Haack Tobias B., Quijano-Roy Susana, Böhm Johann, Nelson Isabelle, Stojkovic Tanya, Evangelista Teresinha, Straub VolkerORCID, Romero Norma B., Laporte JocelynORCID, Muntoni Francesco, Nishino IchizoORCID, Tarnopolsky Mark A.ORCID, Shorter James, Bönnemann Carsten G.ORCID, Taylor J. PaulORCID
Abstract
AbstractMissense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.
Funder
Howard Hughes Medical Institute U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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