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

Hong Joo Kim, Payam Mohassel, Sandra Donkervoort, Lin Guo, Kevin O’Donovan, Maura Coughlin, Xaviere Lornage, Nicola Foulds, Simon R. Hammans, A. Reghan Foley, Charlotte M. Fare, Alice F. Ford, Masashi Ogasawara, Aki Sato, Aritoshi Iida, Pinki Munot, Gautam Ambegaonkar, Rahul Phadke, Dominic G. O’Donovan, Rebecca Buchert, Mona Grimmel, Ana Töpf, Irina T. Zaharieva, Lauren Brady, Ying Hu, Thomas E. Lloyd, Andrea Klein, Maja Steinlin, Alice Kuster, Sandra Mercier, Pascale Marcorelles, Yann Péréon, Emmanuelle Fleurence, Adnan Manzur, Sarah Ennis, Rosanna Upstill-Goddard, Luca Bello, Cinzia Bertolin, Elena Pegoraro, Leonardo Salviati, Courtney E. French, Andriy Shatillo, F. Lucy Raymond, Tobias B. Haack, Susana Quijano-Roy, Johann Böhm, Isabelle Nelson, Tanya Stojkovic, Teresinha Evangelista, Volker Straub, Norma B. Romero, Jocelyn Laporte, Francesco Muntoni, Ichizo Nishino, Mark A. Tarnopolsky, James Shorter, Carsten G. Bönnemann () and J. Paul Taylor ()
Additional contact information
Hong Joo Kim: St. Jude Children’s Research Hospital
Payam Mohassel: National Institutes of Health
Sandra Donkervoort: National Institutes of Health
Lin Guo: Perelman School of Medicine at the University of Pennsylvania
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 Center of Neurology and Psychiatry (NCNP)
Aki Sato: Niigata City General Hospital
Aritoshi Iida: NCNP, Kodaira
Pinki Munot: Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust
Gautam Ambegaonkar: Addenbrookes Hospital
Rahul Phadke: Dubowitz Neuromuscular Centre
Dominic G. O’Donovan: Level 5 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: Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust
Lauren Brady: Hamilton Health Sciences Centre
Ying Hu: National Institutes of Health
Thomas E. Lloyd: Johns Hopkins University School of Medicine
Andrea Klein: University of Bern
Maja Steinlin: University of Bern
Alice Kuster: University Hospital of Nantes
Sandra Mercier: Centre de Référence des Maladies Neuromusculaires AOC
Pascale Marcorelles: Université de Bretagne Occidentale
Yann Péréon: Hôtel-Dieu
Emmanuelle Fleurence: Etablissement de Santé pour Enfants et Adolescents de la région Nantaise
Adnan Manzur: Great Ormond Street Institute of Child Health, 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: IRP Città della Speranza
Elena Pegoraro: University of Padova
Leonardo Salviati: IRP Città della Speranza
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: Centre of Research in Myology
Tanya Stojkovic: Hôpital Pitié-Salpêtrière
Teresinha Evangelista: Hôpital Pitié-Salpêtrière
Volker Straub: Newcastle University and Newcastle Hospitals NHS Foundation Trust
Norma B. Romero: Hôpital Pitié-Salpêtrière
Jocelyn Laporte: Université de Strasbourg
Francesco Muntoni: Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust
Ichizo Nishino: National Center of Neurology and Psychiatry (NCNP)
Mark A. Tarnopolsky: Hamilton Health Sciences Centre
James Shorter: Perelman School of Medicine at the University of Pennsylvania
Carsten G. Bönnemann: National Institutes of Health
J. Paul Taylor: St. Jude Children’s Research Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30015-1

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