The Molecular and Cellular Basis of Hutchinson–Gilford Progeria Syndrome and Potential Treatments

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a rare, autosomal-dominant, and fatal premature aging syndrome. HGPS is most often derived from a de novo point mutation in the LMNA gene, which results in an alternative splicing defect and the generation of the mutant protein, progerin. Progerin behaves in a dominant-negative fashion, leading to a variety of cellular and molecular changes, including nuclear abnormalities, defective DNA damage response (DDR) and DNA repair, and accelerated telomere attrition. Intriguingly, many of the manifestations of the HGPS cells are shared with normal aging cells. However, at a clinical level, HGPS does not fully match normal aging because of the accelerated nature of the phenotypes and its primary effects on connective tissues. Furthermore, the epigenetic changes in HGPS patients are of great interest and may play a crucial role in the pathogenesis of HGPS. Finally, various treatments for the HGPS patients have been developed in recent years with important effects at a cellular level, which translate to symptomatic improvement and increased lifespan.

Scaffold, mechanics and functions of nuclear lamins

“…In humans, the mutation is dominant-negative. This leads to a variety of cellular alterations, including nuclear shape abnormalities, defective DNA damage response (DDR) [73], and accelerated telomere attrition [74,75]. Intriguingly, HGPS cells exhibit several similar phenotypes to natural aging cells [76]; however, they do not entirely match normal aging.…”

Nuclear Phosphoinositides as Key Determinants of Nuclear Functions

“…In response to changes in interactions between cells and the extracellular matrix, mechano-sensation leads to intracellular signalling changes that impact on nuclear morphology and transcriptional output. Changes in nuclear morphology have dramatic impacts on transcriptional output, as exemplified by human mutations in genes that form or control the nuclear lamina leading to early-onset ageing syndromes [166]. How exactly morphological changes impact on transcriptional output is not clear.…”

Progeroide Syndrome

“…Mit der klassischen Progerie wird das Hutchinson-Gilford-Progerie-Syndrom (HGPS) bezeichnet. Bereits im frühen Kindesalter ab 1 bis 2 Jahren beginnen sich die ersten Symptome zu manifestieren [ 16 ]. Betroffene Kinder entwickeln neben Wachstumsverzögerungen ein typisch kleines Gesicht mit einer schnabelartigen Nase, Mikrognathie, Alopezie und typischerweise eine hohe Stimme.…”