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Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy

Lookup NU author(s): Dr Ana TopfORCiD, Dr Teresinha Evangelista, Professor Volker StraubORCiD, Professor John-Paul TaylorORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022, The Author(s). Missense 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.

Publication metadata

Author(s): Kim HJ, Mohassel P, Donkervoort S, Guo L, O'Donovan K, Coughlin M, Lornage X, Foulds N, Hammans SR, Foley AR, Fare CM, Ford AF, Ogasawara M, Sato A, Iida A, Munot P, Ambegaonkar G, Phadke R, O'Donovan DG, Buchert R, Grimmel M, Topf A, Zaharieva IT, Brady L, Hu Y, Lloyd TE, Klein A, Steinlin M, Kuster A, Mercier S, Marcorelles P, Pereon Y, Fleurence E, Manzur A, Ennis S, Upstill-Goddard R, Bello L, Bertolin C, Pegoraro E, Salviati L, French CE, Shatillo A, Raymond FL, Haack TB, Quijano-Roy S, Bohm J, Nelson I, Stojkovic T, Evangelista T, Straub V, Romero NB, Laporte J, Muntoni F, Nishino I, Tarnopolsky MA, Shorter J, Bonnemann CG, Taylor JP

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2022

Volume: 13

Issue: 1

Online publication date: 28/04/2022

Acceptance date: 25/03/2022

Date deposited: 19/05/2022

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group


DOI: 10.1038/s41467-022-30015-1


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Funder referenceFunder name
Institute of Advanced Medical Sciences, Tokushima University (2020, 2A19 to A.I.)
Intramural Research Grant (2-5 and 29-4 to I.N.; 2-5 and 30-9 to A.I.)
National Human Genome Research Institute
MRC Centre for Neuromuscular Diseases Biobank
National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust
NIH National Institute of Neurological Disorders and Stroke
University College London