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Hum Genet. 2005 Dec;118(3-4):444-50. Epub 2005 Oct 6.

Correction of cellular phenotypes of Hutchinson-Gilford Progeria cells by RNA interference.

Author information

1
Department of Pathology, University of Washington, Box 357470, HSB K-543, 1959 NE Pacific Ave, Seattle, WA, 98195-7470, USA.

Abstract

The great majority of cases of the Hutchinson-Gilford progeroid syndrome (HGPS) ("Progeria of Childhood'') are caused by a single nucleotide mutation (1824 C->T) in the LMNA gene which encodes lamin A and C, nuclear intermediate filaments that are important components of the nuclear lamina. The resultant mutant protein (Delta50 lamin A) is thought to act in a dominant fashion. We exploited RNA interference technology to suppress Delta50 lamin A expression, with the long range goal of intervening in the pathogenesis of the coronary artery atherosclerosis that typically leads to the death of HGPS patients. Short hairpin RNA (shRNA) constructs were designed to target the mutated pre-spliced or mature LMNA mRNAs, and were expressed in HGPS fibroblasts carrying the 1824 C->T mutations using lentiviruses. One of the shRNAs targeted to the mutated mRNA reduced the expression levels of Delta50 lamin A to 26% or lower. The reduced expression was associated with amelioration of abnormal nuclear morphology, improvement of proliferative potential, and reduction in the numbers of senescent cells. These findings provide a rationale for potential gene therapy.

PMID:
16208517
DOI:
10.1007/s00439-005-0051-7
[Indexed for MEDLINE]

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