G.P.282: A novel mutation in DNAJB6 causes a more severe phenotype and greater loss of anti-aggregation function

Abstract

LGMD1D (OMIM: #603511) is caused by mutations in the co-chaperone DNAJB6. All reported disease-causing mutations (F89I, F93I, F93L, P96R, and F100I) are located in the G/F-rich domain of DNAJB6. Mutations have so far been identified in European, American and Asian populations. We have now discovered a novel mutation in the G/F-domain of DNAJB6 in a Finnish family with a more severe phenotype than previously reported for DNAJB6 mutations. The age of onset of symptoms was 10 to 12 years of age with weakness in the proximal lower limb muscles and it progressed to upper limbs and to some extent to distal lower limb muscles causing walking difficulties in early adulthood. Respiratory muscles were also involved with this mutation. Two patients had dyspnea and mild to moderate decrease in ventilation and one patient died of respiratory insufficiency at age 33. In this study we investigate the anti-aggregation effect of DNAJB6 in a filter-trap based system using transient transfection of mammalian cell lines and polyQ-huntingtin as a model for an aggregation-prone protein. We here present data for the anti-aggregation effect of all currently known mutations in DNAJB6. The new DNAJB6 mutant protein shows a greater loss of anti-aggregation activity than the other LGMD1D mutations. This loss of activity could be related to the early onset and faster progression seen in these patients.