Journal Article

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

Muntoni, Francesco, Nishino, Ichizo, Physiopathologie des Adaptations Nutritionnelles (PhAN) ; Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE) ; Nantes Université - pôle Santé ; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé ; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), CHRU Brest - Laboratoire d'Anatomo-Pathologie (CHU - AnaPath) ; Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), O’donovan, Kevin, Mohassel, Payam, Marcorelles, Pascale, Quijano-Roy, Susana, Sato, Aki, Brady, Lauren, Fare, Charlotte, M, Phadke, Rahul, Buchert, Rebecca, Bertolin, Cinzia, O’donovan, Dominic, G, Salviati, Leonardo, Klein, Andrea, Foley, A. Reghan, Ford, Alice, F, Taylor, J. Paul, Töpf, Ana, Péréon, Yann, Grimmel, Mona, Ennis, Sarah, Fleurence, Emmanuelle, Shatillo, Andriy, Centre Hospitalier Universitaire de Nantes = Nantes University Hos

2022

Overview

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.

• Publisher: Nature Publishing Group,CCSD,Nature Publishing Group UK,Nature Portfolio
• Subject: 13 / 13/106 / 13/31 / 13/89 / 14 / 14/19 / 14/35 / 631/80/304 / 64 / 64/24 / 692/699/375 / 82/51 / Accumulation / Age / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Animal models / Animals / Binding / Cell culture / Dementia disorders / Disease / Dystrophy / Frameshift Mutation / Frontotemporal dementia / Heterogeneous-Nuclear Ribonucleoprotein Group A-B - genetics / Heterogeneous-Nuclear Ribonucleoprotein Group A-B - metabolism / Heterozygote / Human pathology / Humanities and Social Sciences / Humans / Life Sciences / multidisciplinary / Muscular dystrophy / Muscular Dystrophy, Oculopharyngeal - genetics / Mutation / Myopathy / Nuclear transport / Phenotypes / Proteins / RNA-binding protein / Science / Science (multidisciplinary) / Stop codon
• ISBN: 0007888520000