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Disentangling the mutational effects on protein stability and interaction of human MLH1

ABSTRACT: Disentangling the mutational effects on protein stability and interaction of human MLH1

PROVIDER: PRJNA1142564 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30058408_1.fastq.gz	Fastqsanger.gz
	SRR30058408_2.fastq.gz	Fastqsanger.gz
	SRR30058409_1.fastq.gz	Fastqsanger.gz
	SRR30058409_2.fastq.gz	Fastqsanger.gz
	SRR30058410_1.fastq.gz	Fastqsanger.gz

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Disentangling the mutational effects on protein stability and interaction of human MLH1

Project description:Missense mutations can have diverse effects on proteins, depending on their location within the protein and the specific amino acid substitution. Mutations in the DNA mismatch repair gene MLH1 are associated with Lynch syndrome, yet the underlying mechanism of most disease-causing mutations remain elusive. To address this gap, we aim to disentangle the mutational effects on two essential properties for MLH1 function: protein stability and protein-protein interaction. We systematically examine the cellular abundance and interaction with PMS2 of 4839 (94%) MLH1 variants in the C-terminal domain. Our combined data shows that most MLH1 variants lose interaction with PMS2 due to reduced cellular abundance. However, substitutions to charged residues in the canonical interface lead to reduced interaction with PMS2. Unexpectedly, we also identify a distal region in the C-terminal domain of MLH1 where substitutions cause both decreased and increased binding with PMS2. Our data successfully distinguish benign from pathogenic MLH1 variants and correlate with thermodynamic stability predictions and evolutionary conservation. This work provides mechanistic insights into variant consequences and may help interpret MLH1 variants.

2024-08-01 | GSE273652 | GEO

Highly sensitive MLH1 methylation analysis in blood allows the identification of low-level epigenetic mosaicism

Project description:Constitutional MLH1 epimutations are a rare cause of Lynch syndrome. Low methylation levels (≤10%) have been occasionally described. The aim of this study was the identification of patients with low levels of epigenetic mosaicism in MLH1 gene. Eighteen patients with MLH1 hypermethylated tumors and undetectable methylation in blood as assessed by Methylation-Specific Multiplex Ligation-Dependent Probe Amplification were included (MS-MLPA). Highly sensitive MS-Melting Curve Analysis (MS-MCA) at MLH1 promoter was used to screen for epigenetic mosaicism. Constitutional methylation was confirmed by other methods. Mutational analysis of hereditary cancer genes including MLH1 was performed. MS-MCA analysis identified one case (5.6%) with low levels of methylation (1-2%) in blood DNA. The patient had developed 3 gastrointestinal tumors at ages 22, 24 and 25, sharing MLH1 promoter hypermethylation and loss of heterozygosity associated with c.655A allele. The presence of low MLH1 methylation levels was confirmed by clonal bisulfite sequencing, evidencing the association with c.-93G allele (in phase with c.655G). The extension of the hypermethylated region overlaps with the reported in constitutional MLH1 epimutation carriers. No rare germline variants were identified. The use of highly sensitive techniques such as MS-MCA has demonstrated to be useful for the detection of low MLH1 methylation levels in blood.

2019-05-22 | GSE131541 | GEO

Primary constitutional MLH1 epimutations: a focal epigenetic event [FFPE data sets]

Project description:Background: Constitutional MLH1 epimutations are characterized by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterization of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci. Methods: Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients and 41 healthy controls, were analyzed by Infinium Human Methylation 450K beadchip, and targeted molecular techniques were used to characterize the MLH1 epimutation in carriers and their inheritance pattern. Results: No nucleotide or structural variants were identified in-cis on the epimutated allele in ten carriers, in which intergenerational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls. Conclusion: Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterization is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility.

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Primary constitutional MLH1 epimutations: a focal epigenetic event [blood data sets]

2017-11-28 | GSE107351 | GEO

Deep mutational interaction perturbation reveals ATGL contact sites with key regulatory proteins in lipolysis

Project description:Deep mutational interaction perturbation of ATGL

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The MLH1 c.-27C>A and c.85G>T variants are borne on a European ancestral haplotype which underlies an autosomal dominant form of MLH1 epimutation.

Project description:Lynch syndrome, caused by germline heterozygous mutations of the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2, or deletions affecting the EPCAM gene upstream of MSH2, is characterized by a predisposition to early-onset colorectal and additional extracolonic cancers. An alternative but rare cause of Lynch syndrome is a constitutional epimutation of MLH1, which is characterized by promoter methylation and transcriptional silencing of a single allele in normal tissues. Worldwide, five families with autosomal dominant transmission of a constitutional MLH1 epimutation linked to an MLH1 haplotype with two single nucleotide variants (c.-27C>A and c.85G>T) have been identified. Array-based genotyping using Affymetrix SNP 6.0 data in four of these families revealed a shared haplotype extending across a ≤2.6 Mb region of chromosome 3p22 encompassing MLH1 and additional flanking genes, indicating common ancestry. Genomic DNA from 5 carriers of the c.-27C>A and c.85G>T variants was hybridized on Affymetrix SNP6.0 array according to manufacturer's procedures

2013-04-01 | E-GEOD-45149 | biostudies-arrayexpress

Genome-wide DNA methylation profiling of colorectal tumours from MLH1 epimutation carriers

Project description:Genome-wide DNA methylation analysis of colorectal tumour samples from 44 FFPE tumour and 15 FFPE normal mucosa samples was performed to invesgitate genome-wide DNA methylation signatures that can distinguish MLH1 epimutation carrier CRCs. This was further applied to resolve clinically challenging CRCs including MLH1 promoter VUS carriers and MLH1 methylated EOCRCs

2023-07-01 | GSE233854 | GEO

The MLH1 c.-27C>A and c.85G>T variants are borne on a European ancestral haplotype which underlies an autosomal dominant form of MLH1 epimutation.

2013-04-01 | GSE45149 | GEO

High throughput bisulfite sequencing of the MLH1 promoter in human hematiopoietic progenitor cell clones

Project description:Using single molecule ultra-deep bisulfite sequencing we characterized the CpG methylation landscape from –938 to –337 bp upstream of the MLH1 transcriptional start site position 0, from 30 hematopoietic colony forming cell clones (CFC) either expressing or not expressing MLH1. We identify a correlation between MLH1 promoter methylation and loss of MLH1 expression. Additionally, using the CpG site methylation frequencies obtained in this study we are able to generate a classification algorithm capable of sorting the expressing and non-expressing CFC. Thus, as previously described for many tumor cell types, MLH1 promoter methylation in hematopoietic stem cell clones correlates with the loss of MLH1 expression, a critically important gene in the mismatch repair pathway.

2017-02-09 | GSE73868 | GEO

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2023-10-18 | GSE245485 | GEO

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