title: Progeroid syndrome patients with ZMPSTE24 deficiency could benefit when treated with rapamycin and dimethylsulfoxide.
abstract: Patients with progeroid syndromes such as mandibuloacral dysplasia, type B (MADB) and restrictive dermopathy (RD) harbor mutations in zinc metalloproteinase (ZMPSTE24), an enzyme essential for posttranslational proteolysis of prelamin A to form mature lamin A. Dermal fibroblasts from these patients show increased nuclear dysmorphology and reduced proliferation; however, the efficacy of various pharmacological agents in reversing these cellular phenotypes remains unknown. In this study, fibroblasts from MADB patients exhibited marked nuclear abnormalities and reduced proliferation that improved upon treatment with rapamycin and dimethylsulfoxide but not with other agents, including farnesyl transferase inhibitors. Surprisingly, fibroblasts from an RD patient with a homozygous null mutation inZMPSTE24, resulting in exclusive accumulation of prelamin A with no lamin A on immunoblotting of cellular lysate, exhibited few nuclear abnormalities and near-normal cellular proliferation. An unbiased proteomic analysis of the cellular lysate from RD fibroblasts revealed a lack of processing of vimentin, a cytoskeletal protein. Interestingly, the assembly of the vimentin microfibrils in MADB fibroblasts improved with rapamycin and dimethylsulfoxide. We conclude that rapamycin and dimethylsulfoxide are beneficial for improving nuclear morphology and cell proliferation of MADB fibroblasts. Data from a single RD patient's fibroblasts also suggest that prelamin A accumulation by itself might not be detrimental and requires additional alterations at the cellular level to manifest the phenotype.
authors.affiliation: Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Baris
authors.initials: B
authors.lastname: Akinci
authors.affiliation: Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Shireesha
authors.initials: S
authors.lastname: Sankella
authors.affiliation: Molecular and Cellular Imaging, Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gilpin
authors.affiliation: Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ozono
authors.affiliation: Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Abhimanyu
authors.initials: A
authors.lastname: Garg
authors.affiliation: Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Agarwal
keywords: severe postnatal growth retardation