Characterization of MDPL Fibroblasts Carrying the Recurrent p.Ser605del Mutation in <i>POLD1</i> Gene

D’Apice, Maria Rosaria; Trucco, Federica; Murdocca, Michela; Spitalieri, Paola; Assereto, Stefania; Baratto, Serena; Morcaldi, Guido; Minetti, Carlo; Sangiuolo, Federica; Novelli, Giuseppe

doi:10.1089/dna.2018.4335

Cited by 19 publications

(21 citation statements)

References 26 publications

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“…A previous study has shown that EPHX1 might protect cells from oxidative stress ( Cheong et al, 2009 ). In addition, increased cellular senescence has been functionally linked to fat-related metabolic dysfunction ( Tchkonia et al, 2010 ) and has been observed in a few lipodystrophic syndromes ( Bidault et al, 2013 ; Fiorillo et al, 2018 ). Cellular aging has also been associated with an increased production of reactive oxygen species (ROS) ( Davalli et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence

Gautheron

Morisseau

Chung

et al. 2021

eLife

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Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less-reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remain partly unknown, and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated EPHX1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. Metreleptin therapy had a beneficial effect in one patient. This translational study highlights the importance of epoxide regulation for adipocyte function and provides new insights into the physiological roles of EHs in humans.

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Section: Resultsmentioning

confidence: 99%

EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence

Gautheron

Morisseau

Chung

et al. 2021

eLife

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“…It functionally and physically interacts with WRN during DNA replication and repair (Kamath‐Loeb, Shen, Schmitt, & Loeb, ). Skin fibroblasts of a MDPL patient exhibited increased fractions of senescent markers and persistent DNA damage after genotoxic treatment (Fiorillo et al, ).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes

Maierhofer¹,

Flunkert²,

Oshima

et al. 2019

Aging Cell

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Werner Syndrome (WS) is an adult‐onset segmental progeroid syndrome. Bisulfite pyrosequencing of repetitive DNA families revealed comparable blood DNA methylation levels between classical (18 WRN‐mutant) or atypical WS (3 LMNA‐mutant and 3 POLD1‐mutant) patients and age‐ and sex‐matched controls. WS was not associated with either age‐related accelerated global losses of ALU, LINE1, and α‐satellite DNA methylations or gains of rDNA methylation. Single CpG methylation was analyzed with Infinium MethylationEPIC arrays. In a correspondence analysis, atypical WS samples clustered together with the controls and were clearly separated from classical WS, consistent with distinct epigenetic pathologies. In classical WS, we identified 659 differentially methylated regions (DMRs) comprising 3,656 CpG sites and 613 RefSeq genes. The top DMR was located in the HOXA4 promoter. Additional DMR genes included LMNA, POLD1, and 132 genes which have been reported to be differentially expressed in WRN‐mutant/depleted cells. DMRs were enriched in genes with molecular functions linked to transcription factor activity and sequence‐specific DNA binding to promoters transcribed by RNA polymerase II. We propose that transcriptional misregulation of downstream genes by the absence of WRN protein contributes to the variable premature aging phenotypes of WS. There were no CpG sites showing significant differences in DNA methylation changes with age between WS patients and controls. Genes with both WS‐ and age‐related methylation changes exhibited a constant offset of methylation between WRN‐mutant patients and controls across the entire analyzed age range. WS‐specific epigenetic signatures occur early in life and do not simply reflect an acceleration of normal epigenetic aging processes.

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“…A previous study has shown that EPHX1 might protect cells from oxidative stress (37). In addition, increased cellular senescence has been functionally linked to fat-related metabolic dysfunction (38) and has been observed in a few lipodystrophic syndromes (39, 40). Cellular aging has also been associated with an increased production of reactive oxygen species (ROS) (41).…”

Section: Resultsmentioning

confidence: 99%

EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence

Gautheron

Morisseau

Chung

et al. 2021

Preprint

View full text Add to dashboard Cite

Epoxide hydrolases (EHs) regulate cellular homeostasis through hydrolysis of epoxides to less reactive diols. The first discovered EH was EPHX1, also known as mEH. EH functions remains partly unknown and no pathogenic variants have been reported in humans. We identified two de novo variants located in EPHX1 catalytic site in patients with a lipoatrophic diabetes characterized by loss of adipose tissue, insulin resistance, and multiple organ dysfunction. Functional analyses revealed that these variants led to the protein aggregation within the endoplasmic reticulum and to a loss of its hydrolysis activity. CRISPR-Cas9-mediated Ephx1 knockout (KO) abolished adipocyte differentiation and decreased insulin response. This KO also promoted oxidative stress and cellular senescence, an observation confirmed in patient-derived fibroblasts. A major beneficial effect of metreleptin therapy was observed. This translational study highlights the importance of epoxide regulation for adipocyte function, and provides new insights into the physiological roles of EHs in humans.

show abstract

Characterization of MDPL Fibroblasts Carrying the Recurrent p.Ser605del Mutation in POLD1 Gene

Cited by 19 publications

References 26 publications

EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence

EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence

Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes

EPHX1 mutations cause a lipoatrophic diabetes syndrome due to impaired epoxide hydrolysis and increased cellular senescence

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