PHENOTYPE STUDY IN A MOUSE MODEL OF PROGERIA (TRANSGENIC G609G LMNA) TO EVALUATE DRUGS ABLE TO REDUCE PROGERIN

The purpose of this research is to study the phenotype of transgenic mice lmna G609G that reproduce the human progeria, i.e. the Hutchinson Gilford Progeria Syndrome (HGPS) and to assess the optimal breeding conditions for these animals. Based on these observations the research will continue with the evaluation of drugs able to reduce or eliminate pathological features. HGPS is a rare autosomal dominant condition caused by is a de novo mutation in chromosome 1q21 exon 11 leading to creation of an abnormal splice donor site that results in expression of a truncated, permanently farnesylated prelamin A (precursor of lamin A/C, a component of nuclear lamina inside the nuclear membrane), called progerin. The disease develops in the first year of life with severe premature senescence involving almost all tissues. Patients suffer from delayed growth, short stature, alopecia, skin thinning, loss of subcutaneous fat, midface hypoplasia, osteolysis, atherosclerosis, cardiac failure, stroke. Life expectancy is about 13.5 years. Thus all effects on reproduction and related problems are completely unknown in humans, but they are of utmost importance in experimental animal breeding, particularly regarding the mouse model of progeria. Our study represents the first-ever description of G609G-C57BL mice breeding over long periods, with a special attention to reproduction, weaning, growth, sensitivity to common pathologies and specific symptom expression. The observation has been particularly focused on heterozygous animals which reflect the human genotype.