Hong Joo Kim, St. Jude Children's Research Hospital
Payam Mohassel, National Institutes of Health
Sandra Donkervoort, National Institutes of Health
Lin Guo, Thomas Jefferson UniversityFollow
Kevin O'Donovan, St. Jude Children's Research Hospital
Maura Coughlin, St. Jude Children's Research Hospital
Xaviere Lornage, Université de Strasbourg
Nicola Foulds, University of Southampton
Simon R Hammans, University Hospital Southampton
A Reghan Foley, National Institutes of Health
Charlotte M Fare, Perelman School of Medicine at the University of Pennsylvania
Alice F Ford, Perelman School of Medicine at the University of Pennsylvania
Masashi Ogasawara, National Institute of Neuroscience
Aki Sato, Niigata City General Hospital
Aritoshi Iida, Medical Genome Center
Pinki Munot, University College London, & Great Ormond Street Hospital Trust
Gautam Ambegaonkar, Cambridge University Hospital NHS Trust
Rahul Phadke, University College London Hospitals
Dominic G O'Donovan, John Bonnett Clinical Laboratories Addenbrooke's Hospital
Rebecca Buchert, University of Tuebingen
Mona Grimmel, University of Tuebingen
Ana Töpf, Newcastle University and Newcastle Hospitals NHS Foundation Trust
Irina T Zaharieva, University College London, & Great Ormond Street Hospital Trust
Lauren Brady, McMaster University
Ying Hu, National Institutes of Health
Thomas E Lloyd, Johns Hopkins University School of Medicine
Andrea Klein, Bern University Hospital
Maja Steinlin, Bern University Hospital
Alice Kuster, University Hospital of Nantes
Sandra Mercier, Université de Nantes
Pascale Marcorelles, Université de Bretagne Occidentale
Yann Péréon, Centre de Référence des Maladies Neuromusculaires
Emmanuelle Fleurence, Etablissement de Santé pour Enfants et Adolescents de la région Nantaise
Adnan Manzur, University College London, & Great Ormond Street Hospital Trust
Sarah Ennis, University of Southampton
Rosanna Upstill-Goddard, University of Southampton
Luca Bello, University of Padova
Cinzia Bertolin, University of Padova
Elena Pegoraro, University of Padova
Leonardo Salviati, University of Padova
Courtney E French, University of Cambridge
Andriy Shatillo, Psychiatry and Narcology of NAMS of Ukraine
F Lucy Raymond, University of Cambridge
Tobias B Haack, University of Tuebingen
Susana Quijano-Roy, AP-HP Université Paris-Saclay
Johann Böhm, Université de Strasbourg
Isabelle Nelson, Sorbonne Université
Tanya Stojkovic, Sorbonne Université
Teresinha Evangelista, Sorbonne Université
Volker Straub, Newcastle University and Newcastle Hospitals NHS Foundation Trust
Norma B Romero, Sorbonne Université
Jocelyn Laporte, Université de Strasbourg
Francesco Muntoni, University College London
Ichizo Nishino, National Institute of Neuroscience
Mark A Tarnopolsky, McMaster University
James Shorter, Perelman School of Medicine at the University of Pennsylvania
Carsten G Bönnemann, National Institute of Neurological Disorders and Stroke
J Paul Taylor, Howard Hughes Medical Institute

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This article is the author’s final published version in Nature Communications, Volume 13, Issue 1, April 2022, Article number 2306.

The published version is available at Copyright © Kim et al.


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.

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Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

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