P H Jonson1, J Palmio2, M Johari1, S Penttilä2, A Evilä1, I Nelson3, G Bonne3, N Wiart4, V Meyer4, A Boland4, J-F Deleuze4, C Masson5, T Stojkovic3, F Chapon6, N B Romero7, G Solé8, X Ferrer8, A Ferreiro9,10, P Hackman1, I Richard11, B Udd1,2,12. 1. Folkhälsan Institute of Genetics, University of Helsinki, Medicum, Helsinki, Finland. 2. Neuromuscular Research Center, Tampere University Hospital, University of Tampere, Tampere, Finland. 3. UPMC Univ Paris 06, INSERM UMRS 974, Center of Research in Myology, Institut de Myologie, Sorbonne Universités, Paris, France. 4. Centre National de Recherche en Génomique Humaine (CNRGH), CEA, Evry, France. 5. Bioinformatics Core Facility, INSERM US24/CNRS UMS3633, INSERM UMR 1163, Institut Imagine, Université Paris Descartes - Structure Fédérative de Recherche Necker, Paris, France. 6. INSERM U1075, Neuromuscular Competence Center, CHU Caen, Université de Normandie, Caen, France. 7. Unit of Neuromuscular Morphology, Institute of Myology, UPMC Paris 6, INSERM UMRS 974, Pitié-Salpêtrière Hospital, Paris, France. 8. Neuromuscular Reference Center, CHU Bordeaux, Bordeaux, France. 9. Unité de Biologie Fonctionnelle et Adaptative, Université Paris Diderot/CNRS, Paris, France. 10. Reference Center for Neuromuscular Disorders, Pitié-Salpêtrière Hospital, AP-HP, Paris, France. 11. Généthon INSERM, U951, INTEGRARE Research Unit, University Paris-Saclay, Evry, France. 12. Department of Neurology, Vaasa Central Hospital, Vaasa, Finland.
Abstract
BACKGROUND AND PURPOSE: The aim was to determine the genetic background of unknown muscular dystrophy in five French families. METHODS: Twelve patients with limb girdle muscular dystrophy or distal myopathy were clinically evaluated. Gene mutations were identified using targeted exon sequencing and mutated DNAJB6 was tested in vitro. RESULTS: Five patients presented with distal lower limb weakness whilst others had proximal presentation with a variable rate of progression starting at the mean age of 38.5 years. Two novel mutations (c.284A>T, p.Asn95Ile, two families; and c.293_295delATG, p.Asp98del, one family) as well as the previously reported c.279C>G (p.Phe93Leu, two families) mutation in DNAJB6 were identified. All showed a reduced capacity to prevent protein aggregation. CONCLUSIONS: The mutational and phenotypical spectrum of DNAJB6-caused muscle disease is larger than previously reported, including also dysphagia. The originally reported c.279C>G (p.Phe93Leu) mutation is now identified in four different populations and appears to be a mutational hotspot. Our report confirms that some DNAJB6 mutations cause distal-onset myopathy and hence DNAJB6 defects should be considered broadly in dominant muscular dystrophy families.
BACKGROUND AND PURPOSE: The aim was to determine the genetic background of unknown muscular dystrophy in five French families. METHODS: Twelve patients with limb girdle muscular dystrophy or distal myopathy were clinically evaluated. Gene mutations were identified using targeted exon sequencing and mutated DNAJB6 was tested in vitro. RESULTS: Five patients presented with distal lower limb weakness whilst others had proximal presentation with a variable rate of progression starting at the mean age of 38.5 years. Two novel mutations (c.284A>T, p.Asn95Ile, two families; and c.293_295delATG, p.Asp98del, one family) as well as the previously reported c.279C>G (p.Phe93Leu, two families) mutation in DNAJB6 were identified. All showed a reduced capacity to prevent protein aggregation. CONCLUSIONS: The mutational and phenotypical spectrum of DNAJB6-caused muscle disease is larger than previously reported, including also dysphagia. The originally reported c.279C>G (p.Phe93Leu) mutation is now identified in four different populations and appears to be a mutational hotspot. Our report confirms that some DNAJB6 mutations cause distal-onset myopathy and hence DNAJB6 defects should be considered broadly in dominant muscular dystrophy families.
Authors: Marco Savarese; Jaakko Sarparanta; Anna Vihola; Per Harald Jonson; Mridul Johari; Salla Rusanen; Peter Hackman; Bjarne Udd Journal: Acta Myol Date: 2020-12-01
Authors: Saeed A Bohlega; Sarah Alfawaz; Hussam Abou-Al-Shaar; Hindi N Al-Hindi; Hatem N Murad; Mohamed S Bohlega; Brian F Meyer; Dorota Monies Journal: Acta Myol Date: 2018-09-01