Novel mutations and genotype-phenotype relationships in 107 families with Fukuyama-type congenital muscular dystrophy (FCMD)

Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal recessive disorders in the Japanese population, is characterized by congenital muscular dystrophy in combination with cortical dysgenesis (m icropolygyria), Recently, we identified, on chromosome 9q31, the gene respo nsible for FCMD, which encodes a novel 461 amino acid protein which we have termed fukutin, Most FCMD-bearing chromosomes examined to date (87%) have been derived from a single ancestral founder, whose mutation consisted of a 3 kb retrotransposal insertion in the 3' non-coding region of the fukutin gene. FCMD is the first human disease known to be caused primarily by an an cient retrotransposal integration. We undertook a systematic analysis of th e FCMD gene in 107 unrelated patients, and identified four novel non-founde r mutations in five of them: one missense, one nonsense, one L1 insertion a nd a 1 bp insertion. The frequency of severe phenotypes, including Walker-W alberg syndrome-like manifestations such as hydrocephalus and microphthalmi a, was significantly higher among probands who were compound heterozygotes carrying a point mutation on one allele and the founder mutation on the oth er, than it was among probands who were homozygous for the 3 kb retrotransp oson. Remarkably, we detected no FCMD patients with non-founder (point) mut ations on both alleles of the gene, and suggest that such cases might be em bryonic-lethal. This could explain why few FCMD cases are reported in non-J apanese populations. Our results provided strong evidence that loss of func tion of fukutin is the major cause of FCMD, and appeared to shed some light on the mechanism responsible for the broad clinical spectrum seen in this disease.