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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. (C) 2015 Elsevier B.V. All rights reserved.

Muscle-eye-brain disease belongs to congenital muscular dystrophies with central nervous system abnormalities. The etiology of MEB is still unknown, but abnormal immunoreactivity for laminin-2 has been reported. To evaluate disease progression in muscle tissue, 32 biopsy specimens from 17 muscle-eye-brain patients were analysed. The samples of four patients were studied by immunohistochemical techniques and by quantitative Western blotting. The samples showed a great variation in the muscle pathology. Regenerative fibers and mild fiber size variation were present in over 60%. At infancy, necrotic and regenerative fibers were common, while fat infiltration was the most prominent finding in the age group over five years. In quantitative studies, the amount of laminin alpha 2 chain was clearly reduced to 10-20% of normal. In contrast, laminin beta 2 chain was overexpressed in the Western blotting studies. These findings may reflect a yet unidentified primary disturbance in the basement membrane composition and function.

DNAJB6 was recently identified as a causative gene for limb-girdle muscular dystrophy type 1D (LGMD1D). DNAJB6 belongs to a class of co-chaperones characterized by a J-domain in the N-terminus. To date, six different mutations have been identified in several families from European, North American and Asian countries. The known mutations cause mainly adult onset, slowly progressive proximal muscle weakness, although occasional patients with earlier onset have been reported. The evolution of the disease has been very mild to moderate and respiratory involvement has not been reported. A Finnish family with four affected members, three siblings and their mother, has been studied extensively in the past decade. All patients presented with marked proximal lower limb weakness at the age of 10 to13 years and many reported some weakness from early childhood. Weakness progressed to proximal upper limbs and to some extent also to distal lower limb muscles causing walking difficulties in early adulthood. The mother became wheelchair bound at age 25. Respiratory involvement was a major problem in the family; two sisters had dyspnea in their late teens and their mother died of respiratory failure at age 33. A novel mutation in DNAJB6 was identified in the family as the cause of this very severe, early onset form of LGMD1D. Functional studies of the mutation indicate a more pronounced reduction of the antiaggregation capacity compared to previously known mutations.