Identification of novel disease targets using Functional Genetics approaches

To date, almost 25,000 mammalian genes have been identified, and the main challenge for contemporary genetics is to understand the function of every gene for the identification of novel disease targets and the improvement of treatments in human diseases. The mouse has emerged as the leading model organism for this task because it mimics human diseases and its genome can be easily manipulated. Two complementary functional genetic approaches can be used to generate mouse models. A forward genetics (phenotype to gene) involves the generation of random germline point mutations in the mouse using N-ethyl-N-nitrosourea (ENU), the phenotypic screening of mice for specific defects, and the positional cloning of those heritable mutations. Alternatively, a reverse genetics (gene to phenotype) starts from a known gene and manipulates the genome to create genetically modified mice, such as transgenics and knockouts.

Our lab uses the mouse to model immune, bone and neuromuscular disorders using both forward and reverse genetics approaches. Our current research focuses on the pathogenic mechanisms underlying in RANKL-mediated pathologies such as osteoporosis or osteopetrosis by studying either transgenic mice overexpressing human RANKL or mutant mice carrying a loss-of-function mutation in RANKL gene, respectively. Moreover, using a forward genetics approach we have identified two novel disease targets, SLC25 and DnaJC11, localized in the mitochondria that cause immune impairments and neurological phenotypes in unique mouse models of ataxia and neuromuscular diseases.

Studying RANKL-mediated pathogenic mechanisms
•RANKL-mediated osteopetrosis
•RANKL-mediated osteoporosis

A novel SLC25 member causes autosomal recessive ataxia

A novel DnaJC family member causes neuromuscular disease

Collaborative research