Mutations of MLC1 (KIAA0027), Encoding a Putative Membrane Protein, Cause Megalencephalic Leukoencephalopathy with Subcortical Cysts

Abstract

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive disorder characterized by macrocephaly, deterioration of motor functions with ataxia, and spasticity, eventuating in mental decline. The 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 critical region by linkage analysis of 11 informative families with MLC to a region of approximately 250 kb, containing four known genes. One family with two patients who were siblings did not display linkage between the MLC phenotype and any of the analyzed microsatellite markers on chromosome 22q(tel), suggesting genetic heterogeneity and the existence of at least a second MLC locus. The maximum two-point LOD score for the 11 families was 6.6 at recombination fraction .02. Twelve different mutations in seven informative and six uninformative families were found in one of the candidate genes, KIAA0027, which we renamed "MLC1." The gene encodes a putative membrane protein with eight predicted transmembrane domains. The patients of one family were compound heterozygotes for mutations that both introduced stop codons. The mutations further included frameshifts, splice-acceptor mutations, a putative splice-donor mutation, and amino acid substitutions of residues in predicted transmembrane domains. These data provide strong evidence that mutations of MLC1 cause the disease.

Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

“…MLC is caused by mutations in the MLC1 or GLIALCAM gene 11, 12. GlialCAM is a protein chaperone ensuring the correct membrane localization of MLC1 13.…”

Identification of novel MLC1 mutations in Chinese patients with megalencephalic leukoencephalopathy with subcortical cysts (MLC)

“…3 The MLC1 (GenBank NM_015166) maps to chromosome band 22q13.3; it covers B20 kb of genomic DNA and includes 12 exons. 3 To date, about 68 MLC-relevant mutations of MLC1 have been identified in patients of various ethnic backgrounds (human gene mutation database).…”

“…3 The MLC1 (GenBank NM_015166) maps to chromosome band 22q13.3; it covers B20 kb of genomic DNA and includes 12 exons. 3 To date, about 68 MLC-relevant mutations of MLC1 have been identified in patients of various ethnic backgrounds (human gene mutation database). However, families unlinked to the MLC1 locus have been reported, 3 and the existence of at least one other locus has been hypothesized.…”

“…3 To date, about 68 MLC-relevant mutations of MLC1 have been identified in patients of various ethnic backgrounds (human gene mutation database). However, families unlinked to the MLC1 locus have been reported, 3 and the existence of at least one other locus has been hypothesized. 4,5 Chinese patients with genetic confirmative diagnosis of MLC have never been reported before.…”

Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts

“…“Megalencephalic leukoencephalopathy with subcortical cysts” (MLC; MIM 604004) is a rare childhood‐onset leukodystrophy,1, 2 caused by homozygous recessive mutations in MLC1 3 or GLIALCAM 4. MLC1 is a membrane protein almost exclusively expressed in brain astrocytes 5.…”