Identification of the gene determining Limb Girdle Muscular Dystrophy type 1H

Muscular dystrophies are a group of inherited primary diseases of muscle, characterized by muscle fiber degeneration and clinically by muscle weakness. Classification of muscular dystrophies traditionally has been based on pathologic, clinical, and inheritance patterns (recessive, dominant, X-linked). Over the past 25 years, gene mutation data have begun to dominate differential diagnostic methods. Molecular diagnostic techniques are now available for many of these disorders, although they may be challenging to implement in a systematic manner, and sequencing of multiple genes may be quite costly, with slow turnaround times. However, sequencing technologies are evolving quickly, and it may be possible shortly to sequence all muscular dystrophy genes in a single test at low cost. This assumes, however, specific knowledge of each gene involved. The main goal of the present project is to perform a clinical and genetic study aimed to identify the causing genetic defect of a novel form of limb-girdle muscular dystrophies autosomal dominantly transmitted, LGMD1H. LGMD1H is a form of muscular dystrophy characterized by a slow progression of proximal muscle weakness in both upper and lower limbs affecting several members of a four generations Italian AD pedigree presenting variable expressivity and incomplete penetrance. Interestingly, histochemical and genetic analyses in skeletal muscle suggested the hypothesis of a dysfunction in a mitochondria. Linkage analysis of LGMD1H mapped to a large region of chromosome 3. We propose to take advantage of new technology of human gene sequencing (that is, next-generation sequencing, NGS) to identify causative mutations of LGMD1H.