Novel mutations in DNAJB6 cause LGMD1D and distal myopathy in French families

P H Jonson; J Palmio; M Johari; S Penttilä; A Evilä; I Nelson; G Bonne; N Wiart; V Meyer; A Boland; J-F Deleuze; C Masson; T Stojkovic; F Chapon; N B Romero; G Solé; X Ferrer; A Ferreiro; P Hackman; I Richard; B Udd

doi:10.1111/ene.13598

Novel mutations in DNAJB6 cause LGMD1D and distal myopathy in French families

Eur J Neurol. 2018 May;25(5):790-794. doi: 10.1111/ene.13598. Epub 2018 Mar 30.

Authors

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 Ferreiro^{9

10}, P Hackman¹, I Richard¹¹, B Udd^{1

2

12}

Affiliations

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.

PMID: 29437287
DOI: 10.1111/ene.13598

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.

Keywords: genetic and inherited disorders; myopathies; neuromuscular diseases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Disease Progression
Distal Myopathies / genetics*
Female
France
HSP40 Heat-Shock Proteins / genetics*
Humans
Male
Middle Aged
Molecular Chaperones / genetics*
Muscle Weakness / genetics
Muscular Dystrophies, Limb-Girdle / genetics*
Mutation*
Nerve Tissue Proteins / genetics*
Pedigree
Phenotype

Substances

DNAJB6 protein, human
HSP40 Heat-Shock Proteins
Molecular Chaperones
Nerve Tissue Proteins

Supplementary concepts

Muscular Dystrophy, Limb-Girdle, Type 1D