Noonan syndrome animal model suggests mechanistic bases of gene dosage imbalance-dependent learning disability

CATTANEO V.; SAN MARTIN A.; PAGANI M.R.

Córdoba, Argentina.

Congreso; II Reunión Conjunta SAN/Taller de Neurociencias; 2010

SAN/Taller de Neurociencias

Human genetic disorders caused by gene dosage alterations usually produce learning disability. In the cases of trisomy, many studies have been seeking for the dosage-sensitive genes, such that the phenotype they confer is altered by gene-copy number. Studying the molecular pathogenesis of learning disability of Noonan Syndrome (NS) in a Drosophila model, we identify a potentially novel mechanism causing gene dosage-dependent learning disability. The over expression of different clinical relevant Shp2 alleles (mutations associated with NS), as well as a wild type allele, produced learning disability. Such effect was caused independently of developmental alterations. Interestingly, the gene product of Shp2 was not required for normal learning ability, since the disruption of the endogenous Shp2 gene through RNA-interference (RNAi) did not affect learning ability. The capability of the RNAi to affect its target gene was confirmed by its effect on long-term memory. This evidence supports the idea that even when a gene is not necessary for normal learning, its over expression or an increase in protein function, can lead to learning disability presumably through unspecific interaction with the normal mechanisms.