Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an auto somal recessive disorder characterized by macrocephaly, deterioration of mo tor functions with ataxia, and spasticity, eventuating in mental decline. T he brain appears swollen on magnetic resonance imaging, with diffuse white- matter abnormalities and the invariable presence of subcortical cysts. MLC was recently localized on chromosome 22q(tel). We have narrowed down the cr itical region by linkage analysis of 11 informative families with MLC to a region of similar to 250 kb, containing four known genes. One family with t wo patients who were siblings did not display linkage between the MLC pheno type and any of the analyzed microsatellite markers on chromosome 22q(tel), suggesting genetic heterogeneity and the existence of at least a second ML C locus. The maximum two-point LOD score for the 11 families was 6.6 at rec ombination fraction .02. Twelve different mutations in seven informative an d six uninformative families were found in one of the candidate genes, KIAA 0027, which we renamed "MLC1." The gene encodes a putative membrane protein with eight predicted transmembrane domains. The patients of one family wer e compound heterozygotes for mutations that both introduced stop codons. Th e mutations further included frameshifts, splice-acceptor mutations, a puta tive splice-donor mutation, and amino acid substitutions of residues in pre dicted transmembrane domains. These data provide strong evidence that mutat ions of MLC1 cause the disease.