Novel mutations in DNAJB6 gene cause a very severe early-onset limb-girdle muscular dystrophy 1D disease.
DNAJB6 is the causative gene for limb-girdle muscular dystrophy 1D (LGMD1D). Four different coding missense mutations, p.F89I, p.F93I, p.F93L, and p.P96R, have been reported in families from Europe, North America and Asia. The previously known mutations cause mainly adult-onset proximal muscle weakness with moderate progression and without respiratory involvement. A Finnish family and a British patient have been studied extensively due to a severe muscular dystrophy. The patients had childhood-onset LGMD, loss of ambulation in early adulthood and respiratory involvement; one patient died of respiratory failure aged 32. Two novel mutations, c.271T > A (p.F91I) and c.271T > C (p.F91L), in DNAJB6 were identified by whole exome sequencing as a cause of this severe form of LGMD1D. The results were confirmed by Sanger sequencing. The anti-aggregation effect of the mutant DNAJB6 was investigated in a filter-trap based system using transient transfection of mammalian cell lines and polyQ-huntingtin as a model for an aggregation-prone protein. Both novel mutant proteins show a significant loss of ability to prevent aggregation.
Department of Neurology, Neuromuscular Research Center, University of Tampere and Tampere University Hospital, Tampere, FIN-33014, Finland. Electronic address: johanna.palmio@uta.fi.
Johanna
J
Palmio
Folkhälsan Institute of Genetics and the Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
Per Harald
PH
Jonson
Folkhälsan Institute of Genetics and the Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
Anni
A
Evilä
Department of Neurology, Unit for Neuromuscular Diseases, Helsinki University Central Hospital, Helsinki, Finland.
Mari
M
Auranen
The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Volker
V
Straub
The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Kate
K
Bushby
The John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Anna
A
Sarkozy
Department of Neurology, Unit for Neuromuscular Diseases, Helsinki University Central Hospital, Helsinki, Finland.
Sari
S
Kiuru-Enari
Department of Neurology, Neuromuscular Research Center, University of Tampere and Tampere University Hospital, Tampere, FIN-33014, Finland; Department of Neurology, Seinäjoki Central Hospital, Seinäjoki, Finland.
Satu
S
Sandell
Deparment of Child Neurology, Helsinki University Central Hospital, Helsinki, Finland.
Helena
H
Pihko
Folkhälsan Institute of Genetics and the Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
Peter
P
Hackman
Department of Neurology, Neuromuscular Research Center, University of Tampere and Tampere University Hospital, Tampere, FIN-33014, Finland; Folkhälsan Institute of Genetics and the Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland; Department of Neurology, Vaasa Central Hospital, Vaasa, Finland.
Bjarne
B
Udd
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D005190:Family; D005260:Female; D005387:Finland; D057809:HEK293 Cells; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D055503:Protein Multimerization / Q000235:genetics / Q000502:physiology; D012131:Respiratory Insufficiency / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D012720:Severity of Illness Index; D044465:White People / Q000235:genetics
C485565:DNAJB6 protein, human; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins
Childhood-onset; DNAJB6 gene; Limb-girdle muscular dystrophy