Dataset Information

Status of treatment strategies for Hutchinson-Gilford progeria syndrome with a focus on prelamin: A posttranslational modification.

ABSTRACT: Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature ageing and early death at a mean age of 14.7 years. At the molecular level, HGPS is caused by a de novo heterozygous mutation in LMNA, the gene encoding A-type lamins (mainly lamin A and C) and nuclear proteins, which have important cellular functions related to structure of the nuclear envelope. The LMNA mutation leads to the synthesis of a truncated prelamin A protein (called progerin), which cannot undergo normal processing to mature lamin A. In normal cells, prelamin A processing involves four posttranslational processing steps catalysed by four different enzymes. In HGPS cells, progerin accumulates as a farnesylated and methylated intermediate in the nuclear envelope where it is toxic and causes nuclear shape abnormalities and senescence. Numerous efforts have been made to target and reduce the toxicity of progerin, eliminate its synthesis and enhance its degradation, but as of today, only the use of farnesyltransferase inhibitors is approved for clinical use in HGPS patients. Here, we review the main current strategies that are being evaluated for treating HGPS, and we focus on efforts to target the posttranslational processing of progerin.

SUBMITTER: Chen X

PROVIDER: S-EPMC9795874 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Status of treatment strategies for Hutchinson-Gilford progeria syndrome with a focus on prelamin: A posttranslational modification.

Chen Xue X Yao Haidong H Andrés Vicente V Bergo Martin O MO Kashif Muhammad M

Basic & clinical pharmacology & toxicology 20220714 4

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature ageing and early death at a mean age of 14.7 years. At the molecular level, HGPS is caused by a de novo heterozygous mutation in LMNA, the gene encoding A-type lamins (mainly lamin A and C) and nuclear proteins, which have important cellular functions related to structure of the nuclear envelope. The LMNA mutation leads to the synthesis of a truncated prelamin A protein (called progerin), which cann ...[more]

PMID: 35790078

Similar Datasets

Project description:PurposeChildren with Hutchinson-Gilford progeria syndrome (HGPS), a rare premature aging disease, exhibit extraskeletal calcifications detected by radiographic analysis and on physical examination. The aim of this study was to describe the natural history and pathophysiology of these abnormal calcifications in HGPS, and to determine whether medications and/or supplements tested in clinical trials alter their development.MethodsChildren from two successive clinical trials administering 1) lonafarnib (n = 26) and 2) lonafarnib + pravastatin + zoledronic acid (n = 37) were studied at baseline (pre-therapy), one year on therapy, and at end-of-therapy (3.3-4.3 years after the baseline visit). Calcium supplementation (oral calcium carbonate) was administered during the first year of the second trial and was subsequently discontinued. Information on calcifications was obtained from physical examinations, radiographs, and serum and urinary biochemical measures. The mineral content of two skin-derived calcifications was determined by x-ray diffraction.ResultsExtraskeletal calcifications were detected radiographically in 12/39 (31%) patients at baseline. The odds of exhibiting calcifications increased with age (p = 0.045). The odds were unaffected by receipt of lonafarnib, pravastatin, and zoledronate therapies. However, administration of calcium carbonate supplementation, in conjunction with all three therapeutic agents, significantly increased the odds of developing calcifications (p = 0.009), with the odds plateauing after the supplement's discontinuation. Composition analysis of calcinosis cutis showed hydroxyapatite similar to bone. Although serum calcium, phosphorus, and parathyroid hormone (PTH) were within normal limits at baseline and on-therapy, PTH increased significantly after lonafarnib initiation (p < 0.001). Both the urinary calcium/creatinine ratio and tubular reabsorption of phosphate (TRP) were elevated at baseline in 22/39 (56%) and 31/37 (84%) evaluable patients, respectively, with no significant changes while on-therapy. The mean calcium × phosphorus product (Ca × Pi) was within normal limits, but plasma magnesium decreased over both clinical trials. Fibroblast growth factor 23 (FGF23) was lower compared to age-matched controls (p = 0.03).ConclusionsExtraskeletal calcifications increased with age in children with HGPS and were composed of hydroxyapatite. The urinary calcium/creatinine ratio and TRP were elevated for age while FGF23 was decreased. Magnesium decreased and PTH increased after lonafarnib therapy which may alter the ability to mobilize calcium. These findings demonstrate that children with HGPS with normal renal function and an unremarkable Ca × Pi develop extraskeletal calcifications by an unidentified mechanism that may involve decreased plasma magnesium and FGF23. Calcium carbonate accelerated their development and is, therefore, not recommended for routine supplementation in these children.

Dataset Information

Status of treatment strategies for Hutchinson-Gilford progeria syndrome with a focus on prelamin: A posttranslational modification.

Publications

Status of treatment strategies for Hutchinson-Gilford progeria syndrome with a focus on prelamin: A posttranslational modification.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets