G.P.173 - A novel mutation in DNAJB6 causes LGMD1D in two French families

Abstract

Mutations in the co-chaperone DNAJB6 is the cause of LGMD1D (OMIM: #603511). To date, six different protein level changes have been reported (F89I, F91I, F93I, F93L, P96R, and F100I). Interestingly, all mutations are located in the G/F-rich domain of DNAJB6. The various mutations are found in families of European, American and Asian origin. We here report a novel mutation found in two French families that is also located to the G/F-domain of DNAJB6. Clinical symptoms presented between 35 and 50 years of age with proximal lower limb weakness and difficulty rising from chairs. The pathology is congruent with previously reported LGMD1D mutations with progressive loss of muscle fibers, rimmed vacuoles and cytoplasmic protein aggregates that are observed in muscle biopsies from affected muscles. In a filter-trap based system using transient transfection of mammalian cell lines and polyQ-huntingtin, which is a model for an aggregation-prone protein, the mutant protein shows significant loss of anti-aggregation capacity compared to the wild-type. DNAJB6 is part of the larger chaperonal complex system handling chaperone mediated selective autophagy. Besides the decreased anti-aggregation function of the new mutant, the functions of the whole complex as previously reported are impaired in a dominant fashion by mutant DNAJB6.