DNA damage accumulation and TRF2 degradation in atypical Werner syndrome fibroblasts with LMNA mutations.

[werner syndrome]

Segmental progeroid syndromes are groups of disorders with multiple features suggestive of accelerated aging . One subset of adult-onset progeroid syndromes , referred to as atypical Werner syndrome , is caused by mutations in the LMNA gene , which encodes a class of nuclear intermediate filaments , lamin A /C . We previously described rapid telomere attrition and accelerated replicative senescence in cultured fibroblasts overexpressing mutant lamin A . In this study , we investigated the cellular phenotypes associated with accelerated telomere shortening in LMNA mutant primary fibroblasts . In early passage primary fibroblasts with R 133 L or L 140 R LMNA mutations , shelterin protein components were already reduced while cells still retained telomere lengths comparable to those of controls . There was a significant inverse correlation between the degree of abnormal nuclear morphology and the level of TRF 2 , a shelterin subunit , suggesting a potential causal relationship . Stabilization of the telomeres via the introduction of the catalytic subunit of human telomerase , hTERT (human telomerase reverse transcriptase ), did not prevent degradation of shelterin components , indicating that reduced TRF 2 in LMNA mutants is not mediated by short telomeres . Interestingly , Î³-H 2 AX foci (reflecting double strand DNA damage ) in early passage LMNA mutant primary fibroblasts and LMNA mutant hTERT fibroblasts were markedly increased in non-telomeric regions of DNA . Our results raise the possibility that mutant lamin A /C causes global genomic instability with accumulation of non-telomeric DNA damage as an early event , followed by TRF 2 degradation and telomere shortening .

Diseases
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Diseases presenting "abnormal nuclear morphology" symptom

werner syndrome

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