Browse
Submit Data
Databases
API
Help

Dataset Information

8 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Shifting landscapes of human MTHFR missense-variant effects.

ABSTRACT: Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.

SUBMITTER: Weile J

PROVIDER: S-EPMC8322931 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Unified inference of missense variant effects and gene constraints in the human genome.

Project description:A challenge in medical genomics is to identify variants and genes associated with severe genetic disorders. Based on the premise that severe, early-onset disorders often result in a reduction of evolutionary fitness, several statistical methods have been developed to predict pathogenic variants or constrained genes based on the signatures of negative selection in human populations. However, we currently lack a statistical framework to jointly predict deleterious variants and constrained genes from both variant-level features and gene-level selective constraints. Here we present such a unified approach, UNEECON, based on deep learning and population genetics. UNEECON treats the contributions of variant-level features and gene-level constraints as a variant-level fixed effect and a gene-level random effect, respectively. The sum of the fixed and random effects is then combined with an evolutionary model to infer the strength of negative selection at both variant and gene levels. Compared with previously published methods, UNEECON shows improved performance in predicting missense variants and protein-coding genes associated with autosomal dominant disorders, and feature importance analysis suggests that both gene-level selective constraints and variant-level predictors are important for accurate variant prioritization. Furthermore, based on UNEECON, we observe a low correlation between gene-level intolerance to missense mutations and that to loss-of-function mutations, which can be partially explained by the prevalence of disordered protein regions that are highly tolerant to missense mutations. Finally, we show that genes intolerant to both missense and loss-of-function mutations play key roles in the central nervous system and the autism spectrum disorders. Overall, UNEECON is a promising framework for both variant and gene prioritization.

| S-EPMC7384676 | biostudies-literature

Correction: Unified inference of missense variant effects and gene constraints in the human genome.

Project description:[This corrects the article DOI: 10.1371/journal.pgen.1008922.].

| S-EPMC7842877 | biostudies-literature

Shifting fitness landscapes in response to altered environments.

Project description:The role of adaptation in molecular evolution has been contentious for decades. Here, we shed light on the adaptive potential in Saccharomyces cerevisiae by presenting systematic fitness measurements for all possible point mutations in a region of Hsp90 under four environmental conditions. Under elevated salinity, we observe numerous beneficial mutations with growth advantages up to 7% relative to the wild type. All of these beneficial mutations were observed to be associated with high costs of adaptation. We thus demonstrate that an essential protein can harbor adaptive potential upon an environmental challenge, and report a remarkable fit of the data to a version of Fisher's geometric model that focuses on the fitness trade-offs between mutations in different environments.

| S-EPMC3855258 | biostudies-literature

Heterozygous missense variant in GLI2 impairs human endocrine pancreas development.

Project description:Missense variants are the most common type of coding genetic variants. Their functional assessment is fundamental for defining any implication in human diseases and may also uncover genes that are essential for human organ development. Here, we apply CRISPR-Cas9 gene editing on human iPSCs to study a heterozygous missense variant in GLI2 identified in two siblings with early-onset and insulin-dependent diabetes of unknown cause. GLI2 is a primary mediator of the Hedgehog pathway, which regulates pancreatic β-cell development in mice. However, neither mutations in GLI2 nor Hedgehog dysregulation have been reported as cause or predisposition to diabetes. We establish and study a set of isogenic iPSC lines harbouring the missense variant for their ability to differentiate into pancreatic β-like cells. Interestingly, iPSCs carrying the missense variant show altered GLI2 transcriptional activity and impaired differentiation of pancreatic progenitors into endocrine cells. RNASeq and network analyses unveil a crosstalk between Hedgehog and WNT pathways, with the dysregulation of non-canonical WNT signaling in pancreatic progenitors carrying the GLI2 missense variant. Collectively, our findings underscore an essential role for GLI2 in human endocrine development and identify a gene variant that may lead to diabetes.

| S-EPMC10954617 | biostudies-literature

Heterozygous missense variant in GLI2 impairs human endocrine pancreas development

Project description:To study the impact of an heterozygous missense variant in GLI2 in pancreatic cell differentiation and function, we established a patient-like pluripotent stem cell model. Interestingly, engineered iPSC lines carrying the identified missense variant in the gene GLI2 showed impaired differentiation into endocrine progenitors. To further characterize putative downstream mechanisms underlying the impaired endocrine differentiation of iPSCs, we performed bulk RNA-seq at three stages of differentiation (iPSC, gut tube and endocrine progenitor stages). At early stages (iPSC and gut tube stage), the transcriptome of GLI2-CTRL and GLI2-MUT-derived cells was highly comparable, with only 48 genes significantly dysregulated at gut tube stage. By contrast, differences at the transcriptome level became evident at endocrine progenitor stage [928 genes upregulated and 1070 downregulated in mutant versus control cells].

2024-02-08 | GSE224943 | GEO

Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy.

Project description:We assessed a large consanguineous Pakistani family (PKAB157) segregating early onset low vision problems. Funduscopic and electroretinographic evaluation of affected individuals revealed juvenile cone-rod dystrophy (CRD) with maculopathy. Other clinical symptoms included loss of color discrimination, photophobia and nystagmus. Whole-exome sequencing, segregation and haplotype analyses demonstrated that a transition variant (c.955T>C; p.(Cys319Arg)) in CNGA3 co-segregated with the CRD phenotype in family PKAB157. The ability of CNGA3 channel to influx calcium in response to agonist, when expressed either alone or together with the wild-type CNGB3 subunit in HEK293 cells, was completely abolished due to p.Cys319Arg variant. Western blotting and immunolocalization studies suggest that a decreased channel density in the HEK293 cell membrane due to impaired folding and/or trafficking of the CNGA3 protein is the main pathogenic effect of the p.Cys319Arg variant. Mutant alleles of the human cone photoreceptor cyclic nucleotide-gated channel (CNGA3) are frequently associated with achromatopsia. In rare cases, variants in CNGA3 are also associated with cone dystrophy, Leber's congenital amaurosis and oligo cone trichromacy. The identification of predicted p.(Cys319Arg) missense variant in CNGA3 expands the repertoire of the known genetic causes of CRD and phenotypic spectrum of CNGA3 alleles.

| S-EPMC4666578 | biostudies-literature

The Act1 D10N missense variant impairs CD40 signaling in human B-cells.

Project description:The TRAF3IP2 gene resides within one of at least 63 psoriasis susceptibility loci and encodes Act1, an adapter protein involved in IL-17 receptor and CD40 signaling pathways. TRAF3IP2 is distinctive (among <10% of candidate susceptibility genes) in that a strongly disease-associated variant encodes a missense SNP predicted to be functionally relevant (SNP rs33980500 C/T encoding Act1 pD10N). As assessed by flow cytometry, Act1 protein was expressed at the highest levels in monocytes, with lower levels in T-cells and B-cells. However, monocytes, T-cells and B-cells failed to respond to IL-17A stimulation of PBMC, as measured by flow cytometric determination of NF-κB phospho-p65. As an alternative stimulus, we treated PBMCs with trimerized recombinant human CD40L and assessed p65, p38 and Erk phosphorylation in CD19+ B-cells as a function of D10N genotype. The increase of phosphorylated p65, p38, and Erk was well-correlated across individuals, and CD40L-induced phosphorylation of p65, p38, and Erk was significantly attenuated in B-cells from Act1 D10N homozygotes, compared to heterozygotes and nullizygotes. Our results indicate that the Act1 D10N variant is a relevant genetic determinant of CD40L responsiveness in human B-cells, with the risk allele being associated with lower B-cell responses in an acute signaling context.

| S-EPMC6033699 | biostudies-literature

Multi-omic stratification of the missense variant cysteinome

Project description:Cancer genomes are rife with genetic variants; one key outcome of this variation is gain-of-cysteine, which is the most frequently acquired amino acid due to missense variants in COSMIC. Acquired cysteines are also both driver mutations and sites targeted by precision therapies. However, despite their ubiquity, nearly all acquired cysteines remain uncharacterized. Here, we pair cysteine chemoproteomics—a technique that enables proteome-wide pinpointing of functional, redox sensitive, and potentially druggable residues—with genomics to reveal the hidden landscape of cysteine acquisition. For both cancer and healthy genomes, we find that cysteine acquisition is a ubiquitous consequence of genetic variation that is further elevated in the context of decreased DNA repair. Our chemoproteogenomics platform integrates chemoproteomic, whole exome, and RNA-seq data, with a customized two-stage false detection rate (FDR) error control -based FragPipe-enabled proteomic search, further enabled with a user-friendly FragPipe interface. By deploying chemoproteogenomics across 11 total cell lines, we identify gain of cysteines, including those liganded by electrophilic druglike molecules. Reference cysteines proximal to missense variants were also found to be pervasive, supporting further heretofore untapped opportunities for proteoform-specific chemical probe development campaigns. Many of the identified acquired cysteines, particularly those in mismatch repair deficient (dMMR) cell lines, were found to be predicted to be highly deleterious, providing evidence for likely functional and therapeutic relevance. The sample-matched combinatorial variant databases built into chemoproteogenomics afforded enhanced coverage and enabled identification of highly reactive and ligandable cysteine residues in the highly polymorphic MHC-Class I complexes, including for pathogenic alleles.

2024-10-03 | PXD043879 | Pride

Analysis of the MTHFR C677T variant with migraine phenotypes.

Project description:BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) gene variant C677T has been implicated as a genetic risk factor in migraine susceptibility, particularly in Migraine with Aura. Migraine, with and without aura (MA and MO) have many diagnostic characteristics in common. It is postulated that migraine symptomatic characteristics might themselves be influenced by MTHFR. Here we analysed the clinical profile, migraine symptoms, triggers and treatments of 267 migraineurs previously genotyped for the MTHFR C677T variant. The chi-square test was used to analyse all potential relationships between genotype and migraine clinical variables. Regression analyses were performed to assess the association of C677T with all migraine clinical variables after adjusting for gender. FINDINGS: The homozygous TT genotype was significantly associated with MA (P < 0.0001) and unilateral head pain (P = 0.002). While the CT genotype was significantly associated with physical activity discomfort (P < 0.001) and stress as a migraine trigger (P = 0.002). Females with the TT genotype were significantly associated with unilateral head pain (P < 0.001) and females with the CT genotype were significantly associated with nausea (P < 0.001), osmophobia (P = 0.002), and the use of natural remedy for migraine treatment (P = 0.003). Conversely, male migraineurs with the TT genotype experienced higher incidences of bilateral head pain (63% vs 34%) and were less likely to use a natural remedy as a migraine treatment compared to female migraineurs (5% vs 20%). CONCLUSIONS: MTHFR genotype is associated with specific clinical variables of migraine including unilateral head pain, physical activity discomfort and stress.

| S-EPMC2919563 | biostudies-literature

Multidimensional PTEN missense variant analysis reveals variant subgroups including potential dominant negatives

Project description:Determining the pathogenicity of human genetic variants is a critical challenge, and functional assessment is often the only option. Experimentally characterizing millions of possible missense variants in thousands of clinically important genes will likely require generalizable, scalable assays. We previously developed Variant Abundance by Massively Parallel Sequencing (VAMP-seq), which measures the effects of thousands of missense variants of a protein on intracellular abundance in a single experiment. Here, we reapplied VAMP-seq to quantify the abundances of additional PTEN missense variants which were missing from the original experiment.

2021-09-13 | GSE159469 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data