REACT: a reversible knock-out mouse model to explore treatment strategies for the SETBP1 haploinsufficiency disease
Awardee: Rocco Piazza
Institution: University of Milano - Bicocca
Award Amount: $40,373
Funding Period: February 1, 2021 - January 31, 2022
Summary:
The SETBP1 gene is located on chromosome 18q21.1; it encodes for a protein of 1596 residues with a predicted molecular weight of 170 kD and a predominantly nuclear localization. Genetic abnormalities occurring in the SETBP1 gene are responsible for the onset of two different disorders: 1) SETBP1 haploinsufficiency (SH), a disorder characterized by varying degrees of intellectual disability, developmental as well as speech delays and caused by sub-megabase deletions occurring in SETBP1 locus. 2) Schinzel-Giedion Syndrome (SGS), a rare disease with multiple severe congenital malformations and fatal outcome, caused by de novo, single nucleotide SETBP1 mutations. The pathogenic mechanisms responsible for the onset of SH and SGS are probably tightly connected albeit opposite, as SH is caused by a decrease in SETBP1 protein while SGS is caused by its accumulation. The involvement of the central nervous system in both disorders suggests that SETBP1 itself plays a critical role in this context. Here, we propose to generate and to functionally validate a reversible knock-out mouse model for the SH syndrome. In this model, a blocking cassette flanked with loxP recombination sites would be inserted at intron level in the normal Setbp1 locus by homologous recombination, resulting in a mouse that is unable to express Setbp1 at normal level, therefore mimicking the human SH condition. Then, the usage of specific Cre mouse lines, where the recombinase is either expressed starting from the embryo, only in the adult, or is tamoxifen-inducible, would allow the removal of the blocking cassette and reactivation of the Setbp1 expression at normal levels.
The project herein presented will provide insightful information on the molecular consequences of the reactivation of SETBP1 protein in a knock-out/haploinsufficient model that mimic the SH syndrome. Our new in vivo model will constitute a valuable platform to dissect the molecular mechanisms at the basis of the brain damage following SETBP1 haploinsufficiency and, even more importantly, to study the effect of SETBP1 reactivation at different time-points during the life of the mouse model.