Assignment of the muscle-eye-brain disease gene to 1p32-p34 by linkage analysis and homozygosity mapping

Muscle-eye-brain disease (MEB) is an autosomal recessive disease of unknown etiology characterized by severe mental retardation, ocular abnormalities, congenital muscular dystrophy, and a polymicrogyria-pachygyria-type neuron al migration disorder of the brain. A similar combination of muscle and bra in involvement is also seen in Walker-Warburg syndrome (WWS) and Fukuyama c ongenital muscular dystrophy (FCMD). Whereas the gene underlying FCMD has b een mapped and cloned, the genetic location of the WWS gene is still unknow n. Here we report the assignment of the MEB gene to chromosome 1p32-p34 by linkage analysis and homozygosity mapping in eight families with 12 affecte d individuals. After a genomewide search for linkage in four affected sib p airs had pinpointed the assignment to Ip, the MEB locus was more precisely assigned to a 9-cM interval flanked by markers D1S200 proximally and D1S211 distally. Multipoint linkage analysis gave a maximum LOD score of 6.17 at locus D1S2677. These findings provide a starting point for the positional c loning of the disease gene, which may play an important role in muscle func tion and brain development. It also provides an opportunity to test other c ongenital muscular dystrophy phenotypes, in particular WWS, for linkage to the same locus.