Isolation of a gene for Fukuyama-type congenital muscular dystrophy and genetic diagnosis

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Fukuyama-type congenital muscular dystrophy (FCMD), the second most common form of muscular dystrophy in Japan, is an autosomal recessive severe muscular dystrophy, associated with brain anomalies.1. Following our initial mapping of the FCMD locus to chromosome 9q31-33, we found linkage disequilibrium between FCMD and mfd220 on 9q31 and then constructed the YAC contig encompassing mfd220.2. By using linkage-disequilibrium mapping, we narrowd the candidate region to <100 kb containing D9S2107 and constructed the consmid contig harboring D9S2107.3. We examined haplotypes of FCMD chromosomes at a few loci around D9S2107. The results indicated that 80% of FCMD-bearing chromosomes carried an ancestral haplotype and that 95% of FCMD patients carried ancestral haplotypes homozygously or heterozygously. There were only a few haplotypes other than the founder one. We predicted the gene location extremely proximal to marker E6 by founder-haplotype mapping.4. We screened genomic rearrangements in FCMD using each clone of the cosmid contig around D9S2107 as a probe. A -3 kb insertion was found near the marker E6, which lies -50 kb proximal to D9S2107, in most FCMD chromosomes with the founder haplotype (86%). The frequency of this insertion in normal chromosomes matched well that of FCMD carrier.5. We performed prenatal dianoses of 10 and several FCMD familes. All the results were correct. Also, we conducted genetic diagnosis of 30-40 families. We demonstrated that breaches in the glia limitans may be the primary cause of the micropolygyria in FCMD by pathological study of an FCMD fetus.