Exploring the mechanisms of LMNA mutation in atypical progeria syndrome and severe cardiomyopathy

Abstract Introduction Atypical progeria syndrome (APS) is a rare genetic disorder caused by a mutation in the LMNA gene, leading to lipodystrophy, diabetes, and other complications. Affected individuals typically die between the ages of 40 and 50 due to cardiovascular dysfunction. Genetic and molecular mechanisms of this syndrome are not well understood, prompting an investigation into the LMNA mutation. Purpose We identified a family with three members having APS, associated with severe cardiomyopathy and premature coronary artery disease. These patients carry an LMNA mutation, specifically c.898GA (p.D300N). We investigate cellular morphology and protein expression in the patients' skin fibroblasts compared to the healthy fibroblasts. Additionally, we have developed a model for APS using patient-derived induced pluripotent stem cells (iPSCs) from fibroblasts to explore the cardiac implications of the LMNA mutation and understand its contribution to disease mechanisms. Materials and Methods We obtained skin fibroblasts biopsies from a 42-year-old patient and a 24-year-old healthy control. We assessed the effects of the LMNA mutation through indirect immunofluorescence using Anti-Lamin A + Lamin C antibody to evaluate nuclear morphology, and used Western blots analysis to evaluate Lamin A/C expression level, and to check whether Progerin—a truncated prelamin A— is expressed in patient. We used TUNEL assay to detect apoptosis levels and DNA fragmentation. Additionally, we generated iPSCs from the patient-derived fibroblasts. Results We found significant nuclear morphology abnormalities in patient-derived fibroblasts compared to controls. We found no evidence for progerin accumulation in the patient cells, and did not observe any changes in apoptotic markers (Fig. 1A-C). The generated iPSCs line expressed pluripotent markers and successfully differentiated into multiple germ layers, indicating a stable model for further investigation (Fig. 2). Conclusions The research demonstrates cellular implications of the LMNA mutation in APS and establishes patient-specific iPSC models for exploring disease mechanisms. These findings may facilitate the development of targeted therapeutic strategies for managing cardiovascular and other complications associated with this syndrome.