A novel obesity gene, the gene MO1 (Sakhnin-1 gene)- Mutation and polymorphism study in Palestinian and Qatari obese, diabetic and lean subjects.  And knockout mouse: functional characterization and correction with gene delivery

 

Adel Shalata M.D-Ph.D, - TRDC

Muhammad AabdulGhani M.D-Ph.D  - TRDC

 

Abstract:  Obesity is a multifactorial disorder associated with serious comorbid diseases including diabetes, hypertension and atherosclerotic cardiovascular disease. Although many trait loci have been identified in cohort linkage studies in obese patients, only a few genes (e.g leptin, PROMC, MCR4, UCP3) have been identified and their role in the development of obesity characterized. Recently, using a genomewide screening strategy, we identified a nonsense mutation in a novel obesity gene (designated the MO-1 or the Sakhnin-1 gene) in a large Arabic family living in the north of Israel. We demonstrated that the gene codes for a novel mitochondrial protein and we have generated a mouse strain, the Sakhnin-1 homological gene constitutional knock-out strain, nowadays we are expanding and genotyping the colonies to see if the homozygote will exhibit the morbidly obese phenotype.

In this grant, we propose to study the gene in both human and knockout mice strain: I- We will test the Sakhnin-1 gene (MO-1) for mutations and SNP's in Palestinian and Qatari Obese, diabetic and lean subjects. II- characterize and study the abnormalities in the Sakhnin-1 gene knockout strain: (i) whole body fat and glucose metabolism; (ii) mitochondrial substrate oxidation and ATP generation; (iii) oxygen consumption in skeletal muscle, liver and adipocytes in the Sakhnin-1 gene knockout strain. We also will generate tissue specific knockouts for the gene in skeletal muscle, liver, and brain and study the resultant gene expression profile in order to define the metabolic pathways involved in the development of obesity. Finally, we will examine whether delivering the gene with a unique nano-liposome based delivery system to the knockout mouse will correct identified abnormalities and reverse the obesity.

C: Key words: Sakhnin1 gene, obesity, fat oxidation, mitochondrial function, gene delivery and nanotechnology.

D: Disciplines: Cell biology, Metabolism, Genetics, Nanotechnology