In 2 Finnish brothers with Miyoshi muscular dystrophy-3 (MMD3; 613319), Bolduc et al. (2010) identified a homozygous 2272C-T transition in exon 20 of the ANO5 gene, resulting in an arg758-to-cys (R758C) substitution in a conserved residue in an extracellular loop. The R758C variant was not detected in 100 UK or 208 French Canadian control chromosomes, but was detected in 1 of 368 Finnish control chromosomes, indicating that this variant is present in the Finnish population at a low frequency. The family had originally been reported by Jaiswal et al. (2007).
Among 25 patients, mostly of Finnish descent, with variable muscle disorders due to recessive ANO5 mutations, Penttila et al. (2012) found that R758C was the most common mutation, occurring in homozygous state in 9 Finnish patients and in heterozygous state with another pathogenic allele (see, e.g., 608662.0007 and 608662.0008) in 11 patients. The phenotype was highly variable: 2 females who were homozygous for the mutation had no clinical muscle weakness and only hyperCKemia, whereas other women with the mutation had myalgia and/or calf hypertrophy. Men with the mutation showed distal lower limb weakness or proximal upper and lower limb muscle weakness (LGMDR12; 611307). The findings indicated that this mutation can be associated with a variety of muscle phenotypes.
