SMAD4 mutations and cross-talk between TGF-β/IFNγ signaling accelerate rates of DNA damage and cellular senescence, resulting in a segmental progeroid syndrome-the Myhre syndrome.

ABSTRACT: SMAD4 encodes a member of the SMAD family of proteins involved in the TGF-β signaling pathway. Potentially heritable, autosomal dominant, gain-of-function heterozygous variants of SMAD4 cause a rare developmental disorder, the Myhre syndrome, which is associated with a wide range of developmental and post-developmental phenotypes that we now characterize as a novel segmental progeroid syndrome. Whole-exome sequencing of a patient referred to our International Registry of Werner Syndrome revealed a heterozygous p.Arg496Cys variant of the SMAD4 gene. To investigate the role of SMAD4 mutations in accelerated senescence, we generated cellular models overexpressing either wild-type SMAD4 or mutant SMAD4-R496C in normal skin fibroblasts. We found that cells expressing the SMAD4-R496C mutant exhi

SUBMITTER: Kandhaya-Pillai R 

PROVIDER: S-EPMC8190230 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature