Specific heterozygous frameshift variants in hnRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy - Archive ouverte HAL Access content directly
Preprints, Working Papers, ... Year : 2021

Specific heterozygous frameshift variants in hnRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy

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Hong Joo Kim
Payam Mohassel
  • Function : Author
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 Hammans
  • Function : Author
A. Reghan Foley
  • Function : Author
Charlotte Fare
  • Function : Author
Alice Ford
  • Function : Author
Masashi Ogasawara
  • Function : Author
Aki Sato
  • Function : Author
Aritoshi Iida
Pinki Munot
Gautam Ambegaonkar
  • Function : Author
Rahul Phadke
  • Function : Author
Dominic O’donovan
  • Function : Author
Rebecca Buchert
  • Function : Author
Mona Grimmel
  • Function : Author
Ana Töpf
  • Function : Author
Irina Zaharieva
  • Function : Author
Lauren Brady
  • Function : Author
Ying Hu
  • Function : Author
Thomas Lloyd
  • Function : Author
Andrea Klein
  • Function : Author
Maja Steinlin
  • Function : Author
Sandra Mercier
  • Function : Author
Pascale Marcorelles
  • Function : Author
Yann Péréon
  • Function : Author
Emmanuelle Fleurence
  • Function : Author
Adnan Manzur
  • Function : Author
Sarah Ennis
  • Function : Author
Rosanna Upstill-Goddard
  • Function : Author
Luca Bello
  • Function : Author
Cinzia Bertolin
  • Function : Author
Elena Pegoraro
  • Function : Author
Leonardo Salviati
  • Function : Author
Courtney French
  • Function : Author
Andriy Shatillo
  • Function : Author
F Lucy Raymond
  • Function : Author
Tobias Haack
  • Function : Author
Susana Quijano-Roy
  • Function : Author
Johann Böhm
  • Function : Author
Isabelle Nelson
Tanya Stojkovic
  • Function : Author
Teresinha Evangelista
  • Function : Author
Volker Straub
  • Function : Author
Norma Romero
  • Function : Author
Jocelyn Laporte
  • Function : Author
Francesco Muntoni
Ichizo Nishino
Mark Tarnopolsky
  • Function : Author
James Shorter
J. Paul Taylor
Carsten Bönnemann

Abstract

Summary RNA-binding proteins (RBPs) are essential for post-transcriptional regulation and processing of RNAs. Pathogenic missense variants in RBPs underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, inclusion body myopathy, distal myopathy, and Paget’s disease of the bone. Here, we present ten independent families with a severe, progressive, early-onset muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD), caused by heterozygous frameshift variants in the prion-like domain of hnRNPA2B1 . We found that in contrast with the previously reported missense variants, the frameshift hnRNPA2B1 variants do not promote, but rather decelerate the fibrillization of the protein. Importantly, the frameshift variants harbor altered nuclear-localization sequences and exhibit reduced affinity for the nuclear-import receptor, Karyopherin-β2, which promotes their cytoplasmic accumulation in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with hnRNPA2B1 to include a severe, early-onset disease reminiscent of OPMD, caused by a distinct class of frameshift variants that alter its nucleocytoplasmic transport dynamics.

Dates and versions

hal-03790055 , version 1 (28-09-2022)

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Hong Joo Kim, Payam Mohassel, Sandra Donkervoort, Lin Guo, Kevin O’donovan, et al.. Specific heterozygous frameshift variants in hnRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy. 2022. ⟨hal-03790055⟩
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