Specific 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 Hammans
,
A. Reghan Foley
,
Charlotte Fare
,
Alice Ford
,
Masashi Ogasawara
,
Aki Sato
,
Aritoshi Iida
,
Pinki Munot
,
Gautam Ambegaonkar
,
Rahul Phadke
,
Dominic O’donovan
,
Rebecca Buchert
,
Mona Grimmel
,
Ana Töpf
,
Irina Zaharieva
,
Lauren Brady
,
Ying Hu
,
Thomas Lloyd
,
Andrea Klein
,
Maja Steinlin
,
Alice Kuster
(1, 2)
,
Sandra Mercier
,
Pascale Marcorelles
,
Yann Péréon
,
Emmanuelle Fleurence
,
Adnan Manzur
,
Sarah Ennis
,
Rosanna Upstill-Goddard
,
Luca Bello
,
Cinzia Bertolin
,
Elena Pegoraro
,
Leonardo Salviati
,
Courtney French
,
Andriy Shatillo
,
F Lucy Raymond
,
Tobias Haack
,
Susana Quijano-Roy
,
Johann Böhm
,
Isabelle Nelson
,
Tanya Stojkovic
,
Teresinha Evangelista
,
Volker Straub
,
Norma Romero
,
Jocelyn Laporte
,
Francesco Muntoni
,
Ichizo Nishino
,
Mark Tarnopolsky
,
James Shorter
,
J. Paul Taylor
,
Carsten Bönnemann
Hong Joo Kim
- Function : Author
- PersonId : 1168223
- ORCID : 0000-0002-9157-1612
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
- Function : Author
- PersonId : 1168224
- ORCID : 0000-0001-7538-1651
Pinki Munot
- Function : Author
- PersonId : 1168225
- ORCID : 0000-0001-9900-798X
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
- Function : Author
- PersonId : 1094598
- IdHAL : isabelle-nelson
Tanya Stojkovic
- Function : Author
Teresinha Evangelista
- Function : Author
Volker Straub
- Function : Author
Norma Romero
- Function : Author
Jocelyn Laporte
- Function : Author
Francesco Muntoni
- Function : Author
- PersonId : 759030
- ORCID : 0000-0002-9102-5232
- IdRef : 077207912
Ichizo Nishino
- Function : Author
- PersonId : 1168226
- ORCID : 0000-0001-9452-112X
Mark Tarnopolsky
- Function : Author
James Shorter
- Function : Author
- PersonId : 1168227
- ORCID : 0000-0001-5269-8533
J. Paul Taylor
- Function : Author
- PersonId : 1168228
- ORCID : 0000-0002-5794-0349
- IdRef : 193376237
Carsten Bönnemann
- Function : Author
- PersonId : 1168229
- ORCID : 0000-0002-5930-2324
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.