In-vitro treatment with pravastatin and dexamethasone normalizes abnormal deposition of elastic fibers in dermal fibroblasts derived from patients with Restrictive Dermopathy - Possible therapeutic implications

Poster Presentation: program no. 2153Restrictive dermopathy (RD) is a lethal genodermatosis caused by mutations in lamin A or ZMPSTE24. We hypothesize that potential treatments used in another laminopathy, Hutchinson-Gilford progeria (HGPS), may also produce therapeutic effects in RD. We report the effect of statin and bisphosphonate on the fibroblasts and the surrounding extracellular matrix (ECM) obtained from a fetus with RD. CASE REPORT: The couple was 1st cousins of Pakistani origin with unremarkable family history. They had 2 pregnancies resulting in intra-uterine death at 27-28 weeks, both preceded by decreased fetal movement and oligohydramnios. In the 2nd pregnancy, autopsy revealed classical features of RD and their 1st pregnancy was retrospectively diagnosed with the same condition. IN-VITRO STUDIES: Sequencing of ZMPSTE24 gene showed homozygous p.Glu237Stop mutations in the 2nd fetus. Cultured skin fibroblasts showed abnormal lamin accumulation in the rim of the nuclei. Immuno-histochemistry showed abnormal assembly of elastin fibers due to defective deposition of fibrillin-1. While the RT-PCR showed normal expression of fibrillin-1 mRNA, Western blotting demonstrated peculiar accumulation of pro-fibrillin-1 and proportional deficiency in mature fibrillin-1. This indicates a defective processing of pro-fibrillin-1 to fibrillin-1 which may prevent its assembly into normal microfibrils. Importantly, we found that pravastatin (100μM), but not pamidronate (100μM), ameliorated defective cleavage of pro-fibrillin-1 and improved deposition of microfibrils. Combination of pravastatin and dexamethasone (20μM) lead to further normalization of faulty elastic fibers deposition in the RD fibroblasts. CONCLUSION: Defective nuclear envelope architecture is associated with various phenotypes in laminopathies. There are in-vitro and in-vivo evidence that suggests inhibitors of fernesylation and geranylgeranylation are promising treatment for HGPS. However, for atypical progeria and mandibuloacral dysplasia, data available are so far not supportive. Our finding suggests that ZMPSTE24 deficiency may (indirectly) lead to defective profibrillin-1 processing and prevent the normal assembly of elastic fibers. This may explain the abnormal skin phenotype seen in RD. Our findings also highlight the potential of pravastatin and dexamethasone in alleviating RD phenotype. Further research is required to uncover the mechanism resulting in the correction of the abnormal elastogenesis in RD.The 60th Annual Meeting of the American Society of Human Genetics (ASHG), Washington, DC., 2-6 November 2010