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oai:repisalud.isciii.es:20.500.12105/159122024-09-27T08:17:36Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Chen, Xue author Yao, Haidong author Andres, Vicente author Bergo, Martin O author Kashif, Muhammad author 2022-10 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. Basic Clin Pharmacol Toxicol. 2022 Oct;131(4):217-223. http://hdl.handle.net/20.500.12105/15912 35790078 10.1111/bcpt.13770 1742-7843 Basic & clinical pharmacology & toxicology Status of treatment strategies for Hutchinson-Gilford progeria syndrome with a focus on prelamin: A posttranslational modification.