Enhanced SRSF5 Protein Expression Reinforces Lamin A mRNA Production in HeLa Cells and Fibroblasts of Progeria Patients

ABSTRACT The Hutchinson Gilford Progeria Syndrome (HGPS) is a rare genetic disease leading to accelerated aging. Three mutations of the LMNA gene leading to HGPS were identified. The more frequent ones, c.1824C>T and c.1822G>A, enhance the use of the intron 11 progerin 5′splice site (5′SS) ins...

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Published in:Human mutation 2016-03, Vol.37 (3), p.280-291
Main Authors: Vautrot, Valentin, Aigueperse, Christelle, Oillo-Blanloeil, Florence, Hupont, Sébastien, Stevenin, James, Branlant, Christiane, Behm-Ansmant, Isabelle
Format: Article
Language:English
Subjects:
Aging
alternative splicing
Biochemistry, Molecular Biology
Fibroblasts
Fibroblasts - metabolism
Genetic disorders
HeLa Cells
Human health and pathology
Humans
Hutchinson Gilford Progeria Syndrome
Lamin Type A - genetics
Life Sciences
LMNA
Mutation
PDGF-BB
Progeria - genetics
Progeria - metabolism
Protein expression
Ribonucleic acid
RNA
RNA, Messenger - genetics
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
SRSF1
SRSF5
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Summary:ABSTRACT The Hutchinson Gilford Progeria Syndrome (HGPS) is a rare genetic disease leading to accelerated aging. Three mutations of the LMNA gene leading to HGPS were identified. The more frequent ones, c.1824C>T and c.1822G>A, enhance the use of the intron 11 progerin 5′splice site (5′SS) instead of the LMNA 5′SS, leading to the production of the truncated dominant negative progerin. The less frequent c.1868C>G mutation creates a novel 5′SS (LAΔ35 5′SS), inducing the production of another truncated LMNA protein (LAΔ35). Our data show that the progerin 5′SS is used at low yield in the absence of HGPS mutation, whereas utilization of the LAΔ35 5′SS is dependent upon the presence of the c.1868C>G mutation. In the perspective to correct HGPS splicing defects, we investigated whether SR proteins can modify the relative yields of utilization of intron 11 5′SSs. By in cellulo and in vitro assays, we identified SRSF5 as a direct key regulator increasing the utilization of the LMNA 5′SS in the presence of the HGPS mutations. Enhanced SRSF5 expression in dermal fibroblasts of HGPS patients as well as PDGF‐BB stimulation of these cells decreased the utilization of the progerin 5′SS, and improves nuclear morphology, opening new therapeutic perspectives for premature aging. In the perspective to correct HGPS splicing defects, we investigated whether SR proteins can modify the relative yields of utilization of intron 11 5′SSs. We identified SRSF5 as a direct key regulator increasing the utilization of the LMNA 5′SS in presence of the HGPS mutations. Enhanced SRSF5 expression in dermal fibroblasts of HGPS patients as well as PDGF‐BB stimulation of these cells decreased the utilization of the progerin 5′SS, and improves nuclear morphology, opening new therapeutic perspectives for premature aging.
ISSN:1059-7794
1098-1004
DOI:10.1002/humu.22945