Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy PMID: 35484142

Target-related Cytokines

2026-09-23

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

Nat Commun. 2022 Apr 28;13(1):2306. doi: 10.1038/s41467-022-30015-1.

Hong Joo Kim ^# ¹ , Payam Mohassel ^# ² , Sandra Donkervoort ² , Lin Guo ³ ⁴ , Kevin O'Donovan ¹ , Maura Coughlin ¹ , Xaviere Lornage ⁵ , Nicola Foulds ⁶ , Simon R Hammans ⁷ , A Reghan Foley ² , Charlotte M Fare ³ , Alice F Ford ³ , Masashi Ogasawara ⁸ ⁹ , Aki Sato ¹⁰ , Aritoshi Iida ⁹ , Pinki Munot ¹¹ , Gautam Ambegaonkar ¹² , Rahul Phadke ¹³ , Dominic G O'Donovan ¹⁴ , Rebecca Buchert ¹⁵ , Mona Grimmel ¹⁵ , Ana Töpf ¹⁶ , Irina T Zaharieva ¹¹ , Lauren Brady ¹⁷ , Ying Hu ² , Thomas E Lloyd ¹⁸ , Andrea Klein ¹⁹ ²⁰ , Maja Steinlin ¹⁹ , Alice Kuster ²¹ , Sandra Mercier ²² ²³ , Pascale Marcorelles ²⁴ , Yann Péréon ²⁵ , Emmanuelle Fleurence ²⁶ , Adnan Manzur ¹¹ , Sarah Ennis ²⁷ , Rosanna Upstill-Goddard ²⁷ , Luca Bello ²⁸ , Cinzia Bertolin ²⁹ , Elena Pegoraro ²⁸ , Leonardo Salviati ³⁰ , Courtney E French ³¹ , Andriy Shatillo ³² , F Lucy Raymond ³³ , Tobias B Haack ¹⁵ , Susana Quijano-Roy ³⁴ , Johann Böhm ⁵ , Isabelle Nelson ³⁵ , Tanya Stojkovic ³⁶ , Teresinha Evangelista ³⁷ , Volker Straub ¹⁶ , Norma B Romero ³⁶ ³⁷ , Jocelyn Laporte ⁵ , Francesco Muntoni ¹¹ , Ichizo Nishino ⁸ ⁹ , Mark A Tarnopolsky ¹⁷ , James Shorter ³ , Carsten G Bönnemann ³⁸ , J Paul Taylor ³⁹ ⁴⁰

Affiliations

1. Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, United States.
2. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.
3. Department of Biochemistry & Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.
4. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, United States.
5. Département 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.
6. Wessex Clinical Genetics Services, Princess Anne Hospital, Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, England.
7. Wessex Neurological Centre, University Hospital Southampton, Southampton, UK.
8. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan.
9. Medical Genome Center, NCNP, Kodaira, Tokyo, Japan.
10. Department of Neurology, Niigata City General Hospital, Niigata, Japan.
11. The 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.
12. Department of Paediatric Neurology, Cambridge University Hospital NHS Trust, Addenbrookes Hospital, Cambridge, CB2 0QQ, UK.
13. Division 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.
14. Department of Histopathology Box 235, Level 5 John Bonnett Clinical Laboratories Addenbrooke's Hospital, Cambridge, UK.
15. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
16. John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
17. Division of Neuromuscular & Neurometabolic Disorders, Department of Pediatrics, McMaster University, Hamilton Health Sciences Centre, Hamilton, ON, Canada.
18. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
19. Division of Neuropaediatrics, Development and Rehabilitation, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
20. Pediatric Neurology, University Children's Hospital Basel, University of Basel, Basel, Switzerland.
21. Department of Neurometabolism, University Hospital of Nantes, Nantes, France.
22. CHU Nantes, Service de génétique médicale, Centre de Référence des Maladies Neuromusculaires AOC, 44000, Nantes, France.
23. Université de Nantes, CNRS, INSERM, l'institut du thorax, 44000, Nantes, France.
24. Service d'anatomopathologie, CHU Brest and EA 4685 LIEN, Université de Bretagne Occidentale, Brest, France.
25. CHU de Nantes, Centre de Référence des Maladies Neuromusculaires, Filnemus, Euro-NMD, Hôtel-Dieu, Nantes, France.
26. Etablissement de Santé pour Enfants et Adolescents de la région Nantaise, Nantes, France.
27. Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK.
28. Department of Neurosciences, DNS, University of Padova, Padova, Italy.
29. Clinical Genetics Unit, Department of Women and Children's Health, University of Padova, IRP Città della Speranza, Padova, Italy.
30. Clinical Genetics Unit, Department of Women and Children's Health, CIR-Myo Myology Center, University of Padova, IRP Città della Speranza, Padova, Italy.
31. Department of Paediatrics, University of Cambridge, Cambridge, UK.
32. Institute of Neurology, Psychiatry and Narcology of NAMS of Ukraine, Kharkiv, Ukraine.
33. Cambridge Institute of Medical Research, University of Cambridge, Cambridge, UK.
34. Neuromuscular Unit, Pediatric Neurology and ICU Department, Raymond Poincaré Hospital (UVSQ), AP-HP Université Paris-Saclay, Garches, France.
35. Sorbonne Université, INSERM, Centre of Research in Myology, UMRS974, Paris, France.
36. APHP, Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, Institut de Myologie, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
37. Unité de Morphologie Neuromusculaire, Institut de Myologie, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
38. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States. [email protected].
39. Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, United States. [email protected].
40. Howard Hughes Medical Institute, Chevy Chase, MD, United States. [email protected].
# Contributed equally.

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.