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Lipodystrophy - childhood onset v4.52 EPHX1 Eleanor Williams Tag gene-checked tag was added to gene: EPHX1.
Lipodystrophy - childhood onset v4.52 EPHX1 Achchuthan Shanmugasundram changed review comment from: The rating of this gene has been updated toGreenand the mode of inheritance set toMONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Lipodystrophy - childhood onset v4.52 EPHX1 Achchuthan Shanmugasundram Tag Q3_23_promote_green was removed from gene: EPHX1.
Tag Q3_23_NHS_review was removed from gene: EPHX1.
Lipodystrophy - childhood onset v4.52 EPHX1 Achchuthan Shanmugasundram commented on gene: EPHX1: The rating of this gene has been updated toGreenand the mode of inheritance set toMONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Lipodystrophy - childhood onset v4.51 EPHX1 Achchuthan Shanmugasundram Source Expert Review Green was added to EPHX1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Lipodystrophy - childhood onset v4.34 EPHX1 Achchuthan Shanmugasundram changed review comment from: Two unrelated cases presenting with lipoatrophic diabetes were identified with de novo variants in EPHX1 gene (patient 1: p.Thr333Pro; patient 2: p.Gly430Arg). The disease was characterised by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analysis showed that these variants protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. In addition, CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response.; to: Two unrelated cases presenting with lipoatrophic diabetes were identified with de novo variants in EPHX1 gene (patient 1: p.Thr333Pro; patient 2: p.Gly430Arg). The disease was characterised by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analysis showed that these variants protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. In addition, CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response.

This gene has not yet been associated with relevant phenotypes in OMIM or in Gene2Phenotype.
Lipodystrophy - childhood onset v4.34 EPHX1 Achchuthan Shanmugasundram Tag Q3_23_promote_green tag was added to gene: EPHX1.
Tag Q3_23_NHS_review tag was added to gene: EPHX1.
Lipodystrophy - childhood onset v4.34 EPHX1 Achchuthan Shanmugasundram Classified gene: EPHX1 as Amber List (moderate evidence)
Lipodystrophy - childhood onset v4.34 EPHX1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (two unrelated cases and functional studies) in support of the association of this gene with lipodystrophy and severe insulin resistance. Hence, this gene can be promoted to green rating in the next GMS review.
Lipodystrophy - childhood onset v4.34 EPHX1 Achchuthan Shanmugasundram Gene: ephx1 has been classified as Amber List (Moderate Evidence).
Lipodystrophy - childhood onset v4.33 EPHX1 Achchuthan Shanmugasundram Phenotypes for gene: EPHX1 were changed from Lipodystrophy, Severe Insulin Resistance to lipodystrophy, MONDO:0006573; Insulin resistance, HP:0000855
Lipodystrophy - childhood onset v4.32 EPHX1 Achchuthan Shanmugasundram Publications for gene: EPHX1 were set to
Lipodystrophy - childhood onset v4.31 EPHX1 Achchuthan Shanmugasundram edited their review of gene: EPHX1: Changed rating: GREEN
Lipodystrophy - childhood onset v4.31 EPHX1 Achchuthan Shanmugasundram edited their review of gene: EPHX1: Added comment: Two unrelated cases presenting with lipoatrophic diabetes were identified with de novo variants in EPHX1 gene (patient 1: p.Thr333Pro; patient 2: p.Gly430Arg). The disease was characterised by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analysis showed that these variants protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. In addition, CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response.; Changed publications to: 34342583
Lipodystrophy - childhood onset v4.31 EPHX1 Achchuthan Shanmugasundram changed review comment from: This gene was added on recommendation of NHSE Genomic Medicine Service: EPHX1 is an epoxide hydroxylase, highly expressed in liver and adipose tissue. De novo missense mutations (p.Thr333Pro and p.Gly430Arg) in EPHX1 carried in heterozygosity were implicated in a lipoatrophic diabetes syndrome in two unrelated probands (PMID: 34342583). In vitro characterisation demonstrated loss of enzyme activity in these two mutants and localisation studies demonstrated aggregation of the mutant EPHX1 isoforms in the ER, suggestive of a dominant negative mechanism of action. Consistent with a causal role for EPHX1 in the affected probands' syndrome, circulating epoxy fatty acids were found to be elevated. Variants implicated in the described clinical syndrome caused EPHX1 to form oligomeric complexes and aggregate in the ER. As such it is likely that simple loss of function mutations in EPHX1 do not cause this syndrome, and a dominant negative effect of the EPHX1 mutants is likely the causal mechanism. Consistent with this EPHX1 appears to be LOF tolerant (pLI gnomad = 0, https://gnomad.broadinstitute.org/gene/ENSG00000143819); to: This gene was added on recommendation of NHSE Genomic Medicine Service:
EPHX1 is an epoxide hydroxylase, highly expressed in liver and adipose tissue. De novo missense mutations (p.Thr333Pro and p.Gly430Arg) in EPHX1 carried in heterozygosity were implicated in a lipoatrophic diabetes syndrome in two unrelated probands (PMID: 34342583). In vitro characterisation demonstrated loss of enzyme activity in these two mutants and localisation studies demonstrated aggregation of the mutant EPHX1 isoforms in the ER, suggestive of a dominant negative mechanism of action. Consistent with a causal role for EPHX1 in the affected probands' syndrome, circulating epoxy fatty acids were found to be elevated. Variants implicated in the described clinical syndrome caused EPHX1 to form oligomeric complexes and aggregate in the ER. As such it is likely that simple loss of function mutations in EPHX1 do not cause this syndrome, and a dominant negative effect of the EPHX1 mutants is likely the causal mechanism. Consistent with this EPHX1 appears to be LOF tolerant (pLI gnomad = 0, https://gnomad.broadinstitute.org/gene/ENSG00000143819).
Lipodystrophy - childhood onset v4.3 EPHX1 Achchuthan Shanmugasundram reviewed gene: EPHX1: Rating: ; Mode of pathogenicity: Other; Publications: ; Phenotypes: Lipodystrophy, Severe Insulin Resistance; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Lipodystrophy - childhood onset v4.2 EPHX1 Achchuthan Shanmugasundram gene: EPHX1 was added
gene: EPHX1 was added to Lipodystrophy - childhood onset. Sources: Expert list,NHS GMS
Mode of inheritance for gene: EPHX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: EPHX1 were set to Lipodystrophy, Severe Insulin Resistance
Mode of pathogenicity for gene: EPHX1 was set to Other