MLC1 mutations in Japanese patients with megalencephalic leukoencephalopathy with subcortical cysts

Shimada, Shino; Shimojima, Keiko; Masuda, Teruaki; Nakayama, Yoshiaki; Kohji, Toshihiko; Tsukamoto, Hiroko; Matsubasa, T; Oka, Akira; Yamamoto, Toshiyuki

doi:10.1038/hgv.2014.19

Cited by 9 publications

(5 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…11 Frame shifting mutations were indeed found in many studies underlying these forms of Leukodystrophy. [12][13][14][15] Splicing impairing variants and non-sense variants were also found in our study and from pathogenesis point of view they are even stronger as culprits than either frame shift or missense damaging variants especially for disease which loss of function is their known mechanism 16 . Nonsense variants were found also in other studies [17][18][19] and so are splicing defects.…”

Section: Discussionsupporting

confidence: 75%

Untitled

2018

IJMBOA

View full text Add to dashboard Cite

Megalencephalic Leukodystrophy with sub cortical cysts is a type of Demyelinating Leukodystrophy caused by mutations in MLC1 gene. Various mutations in MLC1 gene have been reported worldwide but high throughput technologies aimed to discover novel variants underlying this disorder are scarce and there is a lot yet to be discovered. In silico analysis of SNPs in a gene known to cause a disease is a well effective and economic method of analyzing known variants deposited in public databases. This article aimed to analyze all SNPs in MLC1 gene in order to be used in screening programs for patients with Megalencephalic Leukodystrophy. The SNPs in MLC1 gene were retrieved from NCBI db SNP. Variants in VCF format were analyzed using Variant Effect Predictor (VEP) of the Ensemble database. The deleterious coding ns SNPs were detected by the web program SIFT, PolyPhen and Mutation Taster in addition to allele frequency and conservation score. The 3-D model of the human MLC1 protein was predicted using the CPH models 2.0 server. The resulting modeled structure with positions of mutations was viewed using Chimera 1.8 software. In MLC1 gene, 4 are nonsense, 18 are indels (frame shift mutations) and 10 potentially disrupt splicing. Six variants in MLC1 gene were predicted to be pathogenic using the same tools. The results of our study will facilitate future studies aimed to analyze the genetics of Leukodystrophy patients from different families from different populations

show abstract

Section: Discussionsupporting

confidence: 75%

Untitled

2018

IJMBOA

View full text Add to dashboard Cite

show abstract

“…The p.Ala275Asp variant was the most prevalent, most common ancestral mutation in the Korean population. Since it was first reported by Montagna et al [ 17 ], this variant has been reported in two Japanese MLC patients [ 17 18 ]. This variant was regarded as the second most common variant in Japanese patients after the p.Ser93Leu variant, which accounts for approximately 80% of Japanese patients with MLC [ 19 ].…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2017

View full text Add to dashboard Cite

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.

show abstract

“…In addition, a 51 year old oligosymptomatic Japanese patient has also been described with mild cognitive and memory deficit, seizures and weakness of the extremities due to a missense mutation, p. Ser93Leu, but not splice site variant of MLC. The first symptom was cognitive impairment when he was 41 years old (20). As mentioned above, several adult cases of MLC have been described that showed atypical or mild symptoms due to MLC1 mutation; but there is not any report of clinically asymptomatic patient.…”

Section: Discussionmentioning

confidence: 99%

An Asymptomatic Case of Megalencephalic Leukoencephalopathy with Subcortical Cysts

et al. 2019

View full text Add to dashboard Cite

Megalencephalic leukoencephalopathy with subcortical cysts (MLC), a demyelination leukodystrophy, is usually characterized by early-onset macrocephaly and gradually progressive motor and mild mental deterioration. Variable clinical expression has been reported in MLC especially in adult cases. In this study, a multi affected family with variable phenotypes including an asymptomatic adult individual is reported to expand the clinical spectrum of MLC. A seven-year old boy was referred to our hospital due to macrocephaly and gait disturbance. According to brain magnetic resonance imaging (MRI) findings, molecular studies were done to confirm the probable diagnosis of MLC in index case followed by family segregation analysis. A homozygous splice site variant, c.177+1G>T in MLC1 gene was found in proband, his mother and two aunts. Aunts were clinically affected but his mother had no clinical symptoms despite bi-allelic mutation in MILC1. The clinical data and available MRI findings were reviewed for these cases. A comprehensive search was conducted on clinical variations of MLC. Phenotypic variability and/or reduced penetrance are important phenomena in MLC. We extended phenotypic variation in MLC by reporting an asymptomatic adult case with a known pathogenic mutation in MLC1 gene.

show abstract

MLC1 mutations in Japanese patients with megalencephalic leukoencephalopathy with subcortical cysts

Cited by 9 publications

References 12 publications

Untitled

Untitled

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

An Asymptomatic Case of Megalencephalic Leukoencephalopathy with Subcortical Cysts

Contact Info

Product

Resources

About