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 5splice site (5SS) instead of the LMNA 5SS, leading to the production of the truncated dominant negative progerin. The less frequent c.1868C>G mutation creates a novel 5SS (LA35 5SS), inducing the production of another truncated LMNA protein (LA35). Our data show that the progerin 5SS is used at low yield in the absence of HGPS mutation, whereas utilization of the LA35 5SS 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 5SSs. By in cellulo and in vitro assays, we identified SRSF5 as a direct key regulator increasing the utilization of the LMNA 5SS 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 5SS, and improves nuclear morphology, opening new therapeutic perspectives for premature aging. (C) 2015 Wiley Periodicals, Inc.