Genetic analysis of limb girdle muscular dystrophy and Miyoshi myopathy

Abstract

The autosomal recessive muscular dystrophies encompass limb girdle muscular dystrophy (LGMD) and Miyoshi myopathy (MM), which can show clinical and genetic overlap. In this study we have made good progress towards understanding the molecular basis of LGMD2I and non-dysferlin MM. Our work on LGMD2I involved haplotype analysis of chromosome 19ql3.3 to identify potential LGMD2I families. We generated a primary transcript map of the LGMD2I region. During this work, mutations in FKRP were described in LGMD2I and MDCIC. In 3 of our families showing potential linkage to 19ql3.3, FKRP mutations were identified. A common mutation in FKRP, C826A (Leu276Ile), is associated with LGMD2I and this mutation was present in 2 of our families and in >70% of the LGMD2I families studied. Genotype-phenotype correlations show this mutation is associated with a milder disease course. FKRP is a predicted glycosyhransferase and mutations in its gene appear to be a common cause of muscular dystrophy. Our work on the analysis of non-dysferlin MM supports the existence of a MM gene, designated MMD2, on chromosome lOp. We have defined a 25Mb region on chromosome 10 shared by affecteds in 2 non-dysferlin MM families. In 5 further families, additional haplotype analysis is required to confirm exclusion from chromosome l0p.In the non-dysferlin MM families haplotype analysis of the caveolin 3 region on chromosome 3 has suggested no involvement of caveolin 3 in non-dysferlin MM. SSCP analysis and sequencing has failed to identify mutation in caveolin 3. The confirmation of the MMD2 gene and identification of recombinant boundaries, allowing candidate gene analysis, will allow us to identify the MMD2 gene.