Modifier genes

Type I disorders of glycosylation (CDG), themost frequent of which is phosphomannomutase
2 (PMM2-CDG), are a group of diseases causing the incomplete N-glycosylation of proteins.
PMM2-CDG is an autosomal recessive disease with a large phenotypic spectrum, and is associated
with mutations in the PMM2 gene. The biochemical analysis of mutants does not allow a precise
genotype–phenotype correlation for PMM2-CDG. PMM2 is very tolerant to missense and loss of
function mutations, suggesting that a partial deficiency of activity might be beneficial under certain
circumstances. The patient phenotype might be influenced by variants in other genes associated with
the type I disorders of glycosylation in the general population.

Limb girdle muscular dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM), a distal muscular dystrophy, are both caused by mutations in the recently cloned gene dysferlin, gene symbol DYSF. Two large pedigrees have been described which have both types of patient in the same families. Moreover, in both pedigrees LGMD2B and MM patients are homozygous for haplotypes of the critical region. This suggested that the same mutation in the same gene would lead to both LGMD2B or MM in these families and that additional factors were needed to explain the development of the different clinical phenotypes. In the present paper we show that in one of these families Pro791 of dysferlin is changed to an Arg residue. Both the LGMD2B and MM patients in this kindred are homozygous for this mutation, as are four additional patients from two previously unpublished families. Haplotype analyses suggest a common origin of the mutation in all the patients. On western blots of muscle, LGMD2B and MM patients show a similar abundance in dysferlin staining of 15 and 11%, respectively. Normal tissue sections show that dysferlin localizes to the sarcolemma while tissue sections from MM and LGMD patients show minimal staining which is indistinguishable between the two types. These findings emphasize the role for the dysferlin gene as being responsible for both LGMD2B and MM, but that the distinction between these two clinical phenotypes requires the identification of additional factor(s), such as modifier gene(s).