Naslov
Mutations of MLC1 (KIAA0027), Encording a Putative Membrane Protein, Cause Megalencephalic Leucoencephalopathy with Subcortical Cysts

Autori
Leegwater, Peter A.J. ; Yuan, Bao Qiang ; van der Steen, Jeffrey ; Mulders, Joyce ; Konst, Andrea A.M. ; Boor, P.K. Ilja ; Mejaški-Bošnjak, Vlatka ; van der Maarel, Silvere M. ; Frants, Rune R. ; Oudejans, Cees B.M. ; Schutgens, Ruud B.H. ; Pronk, Jan C. ; van der Knaap, Marjo S.

Izvornik
American Journal of Human Genetics (0002-9297) 68 (2001); 831-838

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Sažetak
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 resnonance imaging, with diffuse white.matter abnormalities and the invariable presence of subcortical cysts. MLC was recently localized on chromosome 22qtel. We have narrowed down the critical region by linkage analysis of 11 informative families with MLC to region of ~250 kb, containing four known genes. One family with two patients who were sibling did not display linkage between the MLC phenotype and any of the analyzed microsatellite markers on chromosome 22qtel, suggesting genetic heterogeneity and the existance of at least a second MLC locus. The maximum two-point LOD score for the 11 families was 6.6 at recombination fraction .02. Twelwe 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 m,utation, and amino acid substitutions of residues in predicted transmembrane domains. These data provide strong evidence that mutations of MLC1 cause the disease.

Izvorni jezik
Engleski

POVEZANOST RADA