A Unique Mutational Spectrum of MLC1 in Korean Patients With Megalencephalic Leukoencephalopathy With Subcortical Cysts: p.Ala275Asp Founder Mutation and Maternal Uniparental Disomy of Chromosome 22

Abstract

BackgroundMegalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited disorder characterized by infantile-onset macrocephaly, slow neurologic deterioration, and seizures. Mutations in the causative gene, MLC1, are found in approximately 75% of patients and are inherited in an autosomal recessive manner. We analyzed MLC1 mutations in five unrelated Korean patients with MLC.MethodsDirect Sanger sequencing was used to identify MLC1 mutations. A founder effect of the p.Ala275Asp variant was demonstrated by haplotype analysis using single-nucleotide polymorphic (SNP) markers. Multiple ligation-dependent probe amplification (MLPA) and comparative genomic hybridization plus SNP array were used to detect exonic deletions or uniparental disomy (UPD).ResultsThe most prevalent pathogenic variant was c.824C>A (p.Ala275Asp) found in 7/10 (70%) alleles. Two pathogenic frameshift variants were found: c.135delC (p.Cys46Alafs*12) and c.337_353delinsG (p.Ile113Glyfs*4). Haplotype analysis suggested that the Korean patients with MLC harbored a founder mutation in p.Ala275Asp. The p.(Ile113Glyfs*4) was identified in a homozygous state, and a family study revealed that only the mother was heterozygous for this variant. Further analysis of MLPA and SNP arrays for this patient demonstrated loss of heterozygosity of chromosome 22 without any deletion, indicating UPD. The maternal origin of both chromosomes 22 was demonstrated by haplotype analysis.ConclusionsThis study is the first to describe the mutational spectrum of Korean patients with MLC, demonstrating a founder effect of the p.Ala275Asp variant. This study also broadens our understanding of the mutational spectrum of MLC1 by demonstrating a homozygous p.(Ile113Glyfs*4) variant resulting from UPD of chromosome 22.

Homozygous variant of MLC1 results in megalencephalic leukoencephalopathy with subcortical cysts

“…term= MLC1% 5Bgene% 5D& redir= gene). Notably, only two deletion-insertion (delins) variants are reported (Choi et al, 2017;Leegwater et al, 2001;Tsujino et al, 2003), and both of them resulted in MLC1 loss of function.…”

“…Currently, a total of 88 likely pathogenic or pathogenic variants have been collected in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/?term=MLC1%5Bgene%5D%26redir=gene). Notably, only two deletion–insertion (delins) variants are reported (Choi et al., 2017; Leegwater et al., 2001; Tsujino et al., 2003), and both of them resulted in MLC1 loss of function.…”

Transmembrane topology and oligomeric nature of an astrocytic membrane protein, MLC1

“…Mutations in the MLC1 protein can cause a neurological disorder named MLC disease. More than 50 MLC1 mutations, including splice-site, nonsense, missense, deletion and insertion mutations, have been reported [47][48][49][50], and 35 of these mutations are caused by single amino acid substitutions. Interestingly, 27 of these mutations were in the predicted TM domains, and four were closely adjacent to the TM domains (electronic supplementary material, figure S2, red and magenta letters, respectively).…”

Megalencephalic leukoencephalopathy with subcortical cysts: a variant update and review of the literature

“…c.176G>A; p.(Gly59Glu) is a possible founder variant in Libyan Jews ( Ben-Zeev et al, 2002 ). c.278C>T; p.(Ser93Leu) is common in Japanese individuals ( Shimada et al, 2014 ), while c.824C>A; p.(Ala275Asp) is a founder variant accounting for the majority of MLC patients of Korean ancestry ( Choi et al, 2017 ). c.908_918delinsGCA; p.(Val303Glyfs*96) is a founder variant in individuals with Egyptian ancestry.…”