Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy - INRAE - Institut national de recherche pour l’agriculture, l’alimentation et l’environnement Access content directly
Journal Articles Nature Communications Year : 2022

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

Hong Joo Kim
Payam Mohassel
Sandra Donkervoort
  • Function : Author
Lin Guo
  • Function : Author
Kevin O’donovan
  • Function : Author
Maura Coughlin
  • Function : Author
Xaviere Lornage
  • Function : Author
Nicola Foulds
  • Function : Author
Simon R Hammans
  • Function : Author
A. Reghan Foley
  • Function : Author
Charlotte M Fare
Alice F Ford
  • Function : Author
Masashi Ogasawara
  • Function : Author
Aki Sato
  • Function : Author
Aritoshi Iida
Pinki Munot
  • Function : Author
Gautam Ambegaonkar
  • Function : Author
Rahul Phadke
  • Function : Author
Dominic G O’donovan
  • Function : Author
Rebecca Buchert
Mona Grimmel
  • Function : Author
Ana Töpf
  • Function : Author
Irina T Zaharieva
  • Function : Author
Lauren Brady
  • Function : Author
Ying Hu
  • Function : Author
Thomas E Lloyd
Andrea Klein
  • Function : Author
Maja Steinlin
  • Function : Author
Sandra Mercier
  • Function : Author
Pascale Marcorelles
  • Function : Author
Yann Péréon
  • Function : Author
Emmanuelle Fleurence
Adnan Manzur
  • Function : Author
Sarah Ennis
Rosanna Upstill-Goddard
Luca Bello
Cinzia Bertolin
  • Function : Author
Elena Pegoraro
  • Function : Author
Leonardo Salviati
Courtney E French
Andriy Shatillo
F. Lucy Raymond
Tobias B Haack
  • Function : Author
Susana Quijano-Roy
  • Function : Author
Johann Böhm
  • Function : Author
Isabelle Nelson
Tanya Stojkovic
  • Function : Author
Teresinha Evangelista
  • Function : Author
Volker Straub
Norma B Romero
  • Function : Author
Jocelyn Laporte
Francesco Muntoni
  • Function : Author
Ichizo Nishino
Mark A Tarnopolsky
James Shorter
  • Function : Author
Carsten G Bönnemann
J. Paul Taylor

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.
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hal-03978696 , version 1 (08-02-2023)

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Hong Joo Kim, Payam Mohassel, Sandra Donkervoort, Lin Guo, Kevin O’donovan, et al.. Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy. Nature Communications, 2022, 13 (1), pp.2306. ⟨10.1038/s41467-022-30015-1⟩. ⟨hal-03978696⟩
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