ArticleNature communications2022
Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy.
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29 citing papers in PubMed.
- Oculopharyngeal Muscular Dystrophy: From Molecular Pathogenesis to Gene Therapy.Molecular neurobiology · 2026Review
- Neurodegenerative-related gene rescue in anterior insula after early life maltreatment restores adult social interaction in male mice.Molecular psychiatry · 2026Article
- Impaired Myogenic Differentiation Is a Shared Feature Across Genetic Myopathies.International journal of molecular sciences · 2026Review
- Pathological disruption of CELF2 shuttling causes neuronal hyperactivity, learning deficits, and seizures.The Journal of clinical investigation · 2026Article
- HnRNPA2B1 tunes antimycobacterial immune responses in macrophages through alternative splicing ofInfection and immunity · 2026Article
- Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains.Molecular cell · 2026Article
- HnRNPA2B1 tunes antimycobacterial immune responses in macrophages through alternative splicing ofbioRxiv : the preprint server for biology · 2025Article
- Nuclear-import receptors remodel the dilute phase to suppress phase transitions of RNA-binding proteins with prion-like domains.bioRxiv : the preprint server for biology · 2025Article
- In-Depth Study of Low-Complexity Domains: From Structural Diversity to Disease Mechanisms.Cells · 2025Review
- Cytoplasmic accumulation of a splice variant of hnRNPA2/B1 contributes to FUS-associated toxicity in a mouse model of ALS.Cell death & disease · 2025Article
- Article
- Review
- Nuclear pore dysfunction and disease: a complex opportunity.Nucleus (Austin, Tex.) · 2024Review
- Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches.Disease models & mechanisms · 2024Review
- Epigenetic modulators provide a path to understanding disease and therapeutic opportunity.Genes & development · 2024Review
- Review
- Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.Molecular neurodegeneration · 2024Review
- HNRNPA1 de novo Variant Associated with Early Childhood Onset, Rapidly Progressive Generalized Myopathy.Journal of neuromuscular diseases · 2024Article
- aenmd: annotating escape from nonsense-mediated decay for transcripts with protein-truncating variants.Bioinformatics (Oxford, England) · 2023Article
- Regulation of Atp7a RNA contributes to differentiation-dependent Cu redistribution in skeletal muscle cells.Metallomics : integrated biometal science · 2023Article
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Authors and funding
58 authors.
Hong Joo Kim *Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, United States.ORCID 0000-0002-9157-1612
Payam Mohassel *National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.ORCID 0000-0001-5313-9514
Sandra DonkervoortNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.
Lin GuoDepartment of Biochemistry & Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.
Kevin O'DonovanDepartment of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, United States.
Maura CoughlinDepartment of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, United States.
Xaviere LornageDépartement Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U1258, Centre National de la Recherche Scientifique UMR7104, Université de Strasbourg, Illkirch, France.
Nicola FouldsWessex Clinical Genetics Services, Princess Anne Hospital, Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, England.
Simon R HammansWessex Neurological Centre, University Hospital Southampton, Southampton, UK.
A Reghan FoleyNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.
Charlotte M FareDepartment of Biochemistry & Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.ORCID 0000-0003-0394-6435
Alice F FordDepartment of Biochemistry & Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.
Masashi OgasawaraDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.
Aki SatoDepartment of Neurology, Niigata City General Hospital, Niigata, Japan.
Aritoshi IidaMedical Genome Center, NCNP, Kodaira, Tokyo, Japan.ORCID 0000-0001-7538-1651
Pinki MunotThe Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, UK.
Gautam AmbegaonkarDepartment of Paediatric Neurology, Cambridge University Hospital NHS Trust, Addenbrookes Hospital, Cambridge, CB2 0QQ, UK.
Rahul PhadkeDivision of Neuropathology, University College London Hospitals NHS Foundation Trust National Hospital for Neurology and Neurosurgery London, UK and Division of Neuropathology, UCL Institute of Neurology, Dubowitz Neuromuscular Centre, London, UK.
Dominic G O'DonovanDepartment of Histopathology Box 235, Level 5 John Bonnett Clinical Laboratories Addenbrooke's Hospital, Cambridge, UK.
Rebecca BuchertInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.ORCID 0000-0001-7576-3326
Mona GrimmelInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Ana TöpfJohn Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Irina T ZaharievaThe Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, UK.
Lauren BradyDivision of Neuromuscular & Neurometabolic Disorders, Department of Pediatrics, McMaster University, Hamilton Health Sciences Centre, Hamilton, ON, Canada.
Ying HuNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.
Thomas E LloydDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.ORCID 0000-0003-4756-3700
Andrea KleinDivision of Neuropaediatrics, Development and Rehabilitation, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Maja SteinlinDivision of Neuropaediatrics, Development and Rehabilitation, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Alice KusterDepartment of Neurometabolism, University Hospital of Nantes, Nantes, France.
Sandra MercierCHU Nantes, Service de génétique médicale, Centre de Référence des Maladies Neuromusculaires AOC, 44000, Nantes, France.
Pascale MarcorellesService d'anatomopathologie, CHU Brest and EA 4685 LIEN, Université de Bretagne Occidentale, Brest, France.
Yann PéréonCHU de Nantes, Centre de Référence des Maladies Neuromusculaires, Filnemus, Euro-NMD, Hôtel-Dieu, Nantes, France.
Emmanuelle FleurenceEtablissement de Santé pour Enfants et Adolescents de la région Nantaise, Nantes, France.ORCID 0000-0002-6717-3737
Adnan ManzurThe Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, UK.
Sarah EnnisHuman Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.ORCID 0000-0003-2648-0869
Rosanna Upstill-GoddardHuman Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.ORCID 0000-0002-2666-0934
Luca BelloDepartment of Neurosciences, DNS, University of Padova, Padova, Italy.ORCID 0000-0002-3075-6525
Cinzia BertolinClinical Genetics Unit, Department of Women and Children's Health, University of Padova, IRP Città della Speranza, Padova, Italy.
Elena PegoraroDepartment of Neurosciences, DNS, University of Padova, Padova, Italy.
Leonardo SalviatiClinical Genetics Unit, Department of Women and Children's Health, CIR-Myo Myology Center, University of Padova, IRP Città della Speranza, Padova, Italy.ORCID 0000-0001-5642-9963
Courtney E FrenchDepartment of Paediatrics, University of Cambridge, Cambridge, UK.ORCID 0000-0001-7620-1544
Andriy ShatilloInstitute of Neurology, Psychiatry and Narcology of NAMS of Ukraine, Kharkiv, Ukraine.ORCID 0000-0003-3630-6880
F Lucy RaymondCambridge Institute of Medical Research, University of Cambridge, Cambridge, UK.ORCID 0000-0003-2652-3355
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
Susana Quijano-RoyNeuromuscular Unit, Pediatric Neurology and ICU Department, Raymond Poincaré Hospital (UVSQ), AP-HP Université Paris-Saclay, Garches, France.
Johann BöhmDépartement Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U1258, Centre National de la Recherche Scientifique UMR7104, Université de Strasbourg, Illkirch, France.
Isabelle NelsonSorbonne Université, INSERM, Centre of Research in Myology, UMRS974, Paris, France.
Tanya StojkovicAPHP, Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, Institut de Myologie, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Teresinha EvangelistaUnité de Morphologie Neuromusculaire, Institut de Myologie, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Volker StraubJohn Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.ORCID 0000-0001-9046-3540
Norma B RomeroAPHP, Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, Institut de Myologie, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
Jocelyn LaporteDépartement Médecine Translationnelle et Neurogénétique, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale U1258, Centre National de la Recherche Scientifique UMR7104, Université de Strasbourg, Illkirch, France.ORCID 0000-0001-8256-5862
Francesco MuntoniThe Dubowitz Neuromuscular Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, UK.
Ichizo NishinoDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.ORCID 0000-0001-9452-112X
Mark A TarnopolskyDivision of Neuromuscular & Neurometabolic Disorders, Department of Pediatrics, McMaster University, Hamilton Health Sciences Centre, Hamilton, ON, Canada.ORCID 0000-0003-0312-3746
James ShorterDepartment of Biochemistry & Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.
Carsten G BönnemannNational Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States. carsten.bonnemann@nih.gov.ORCID 0000-0002-5930-2324
J Paul TaylorDepartment of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, United States. jpaul.taylor@stjude.org.ORCID 0000-0002-5794-0349
Funding
Molecular and Clinical Manifestations of Matrix and Aggregate MyopathiesZIANS003129 · NINDS · NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE · PI BÖNNEMANN, CARSTEN · 2011 to 2025
$52.8MJoint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MTraining in Alzheimer’s and Age-Related Neurodegenerative DiseasesT32AG000255 · NIA · UNIVERSITY OF PENNSYLVANIA · PI ALICE S CHEN-PLOTKIN, VIRGINIA M LEE · 1997 to 2026
$12.5MDynamic RNA-protein assemblies and neurological diseaseR35NS097974 · NINDS · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI TAYLOR, JOSEPH PAUL · 2017 to 2024
$7.2MSTRUCTURAL BIOLOGY TRAINING PROGRAMT32GM008275 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI WAND, A. JOSHUA · 1988 to 2018
$6.0MDefining the mechanistic basis of a prion disaggregaseR01GM099836 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI SHORTER, JAMES · 2013 to 2024
$3.9MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MEngineering KapB2 to Disaggregate Disease-Linked ProteinsF31NS111870 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI FARE, CHARLOTTE MIRIAM · 2019 to 2021
$137kMechanisms and modifiers of hnRNPA1 and hnRNPA2 misfolding and toxicityF31NS087676 · NINDS · UNIVERSITY OF PENNSYLVANIA · PI FORD, ALICE FLYNN · 2014 to 2016
$77kDepartment of HealthHoward Hughes Medical InstituteMedical Research CouncilNHGRI NIH HHS R01 HG009141NHGRI NIH HHS UM1 HG008900NIA NIH HHS T32 AG000255NIGMS NIH HHS R01 GM099836NIGMS NIH HHS T32 GM008275NINDS NIH HHS F31 NS087676NINDS NIH HHS F31 NS111870NINDS NIH HHS R35 NS097974
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.
Indexed as
Amyotrophic Lateral SclerosisMuscular Dystrophy, OculopharyngealAnimalsFrameshift MutationHeterogeneous-Nuclear Ribonucleoprotein Group A-BHeterozygoteHumansHeterogeneous-Nuclear Ribonucleoprotein Group A-BHNRNPA3 protein, human
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