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

Authors

• 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

Document Type

Article

Publication Date

4-28-2022

Comments

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 https://doi.org/10.1038/s41467-022-30015-1. Copyright © Kim et al.

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.

Recommended Citation

Kim, Hong Joo; Mohassel, Payam; Donkervoort, Sandra; Guo, Lin; O'Donovan, Kevin; Coughlin, Maura; Lornage, Xaviere; Foulds, Nicola; Hammans, Simon R; Foley, A Reghan; Fare, Charlotte M; Ford, Alice F; Ogasawara, Masashi; Sato, Aki; Iida, Aritoshi; Munot, Pinki; Ambegaonkar, Gautam; Phadke, Rahul; O'Donovan, Dominic G; Buchert, Rebecca; Grimmel, Mona; Töpf, Ana; Zaharieva, Irina T; Brady, Lauren; Hu, Ying; Lloyd, Thomas E; Klein, Andrea; Steinlin, Maja; Kuster, Alice; Mercier, Sandra; Marcorelles, Pascale; Péréon, Yann; Fleurence, Emmanuelle; Manzur, Adnan; Ennis, Sarah; Upstill-Goddard, Rosanna; Bello, Luca; Bertolin, Cinzia; Pegoraro, Elena; Salviati, Leonardo; French, Courtney E; Shatillo, Andriy; Raymond, F Lucy; Haack, Tobias B; Quijano-Roy, Susana; Böhm, Johann; Nelson, Isabelle; Stojkovic, Tanya; Evangelista, Teresinha; Straub, Volker; Romero, Norma B; Laporte, Jocelyn; Muntoni, Francesco; Nishino, Ichizo; Tarnopolsky, Mark A; Shorter, James; Bönnemann, Carsten G; and Taylor, J Paul, "Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy" (2022). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 216.
https://jdc.jefferson.edu/bmpfp/216

Creative Commons License

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

PubMed ID

35484142

Language

English