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

Published version
Peer-reviewed

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Type

Article

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Authors

Donkervoort, Sandra 
Guo, Lin 
O'Donovan, Kevin 

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.

Description

Funder: Howard Hughes Medical Institute

Keywords

Amyotrophic Lateral Sclerosis, Animals, Frameshift Mutation, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Heterozygote, Humans, Muscular Dystrophy, Oculopharyngeal

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

13

Publisher

Springer Science and Business Media LLC
Sponsorship
U.S. Department of Health &amp (R35NS097974)
U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) (R35NS097974)
Telethon (GTB12001D)