期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-30015-1
关键词
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资金
- NIH National Institute of Neurological Disorders and Stroke
- Clinical Center Genomics Opportunity - National Human Genome Research Institute
- NIH Deputy Director for Intramural Research
- NIH Clinical Center
- Howard Hughes Medical Institute [R35NS097974]
- ALS Association [18-IIA-419]
- NCNP [2-5, 29-4, 30-9]
- AMED [20ek0109490h0001, JP19ek0109285h0003]
- Joint Usage and Joint Research Programs
- Institute of Advanced Medical Sciences, Tokushima University
- National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London
- MRC Centre for Neuromuscular Diseases Biobank
- HSS England Diagnostic and Advisory Service for Congenital Myopathies and Congenital Muscular Dystrophies in London, UK
- European Community [FP7/2007-2013, 2012-305121]
- European Reference Network for Neuromuscular Diseases [870177]
- Telethon Network of Genetic BioBank [GTB12001D]
- EuroBioBank network
- France Genomique National infrastructure
- Fondation Maladies Rares within the frame of the Myocapture sequencing project
- Association Francaise contre les Myopathies [22734]
- Cambridge NIHR Biomedical Research Centre
- Rosetree Foundation
- Ellison Medical Foundation/American Federation for Aging Research fellowship
- Alzheimer's Association Research fellowship
- Target ALS Springboard Fellowship
- NIH [T32GM008275, F31NS111870, T32AG00255, F31NS087676, R01GM099836]
- Target ALS, Packard Foundation
- ALS Association
- G. Harold and Leila Y. Mathers Charitable Foundation
- Sanofi Genzyme
- Ultragenyx
- LGMD2I Research Fund
- Samantha J. Brazzo Foundation
- LGMD2D Foundation
- Kurt+Peter Foundation
- Muscular Dystrophy UK
- Coalition to Cure Calpain 3
- National Human Genome Research Institute
- National Eye Institute
- National Heart, Lung, and Blood Institute [UM1 HG008900]
- National Human Genome Research Institute [R01HG009141]
The study describes a severe and progressive muscular dystrophy caused by heterozygous frameshift mutations in the RNA-binding protein HNRNPA2B1. These mutations alter the nucleocytoplasmic transport dynamics of the protein, leading to cytoplasmic accumulation. This expands the understanding of the phenotypes associated with HNRNPA2B1 and highlights the importance of nucleocytoplasmic transport in disease pathology.
Missense variants in RNA-binding proteins underlie many diseases. Here the authors report an oculopharyngeal muscular dystrophy caused by heterozygous frameshift mutations in HNRNPA2B1 that alter its nucleocytoplasmic transport dynamics and result in cytoplasmic accumulation of hnRNPA2 protein. 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 beta 2, 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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