Causative mutations of Mendelian disease can be identified using exome sequencing of patient samples, but the presence of rare variants can prevent loci identification. To circumvent these difficulties, mutations from a Drosophila forward genetic screen that identified genes involved in neurodegeneration or neurodevelopment were used to screen a human exome database for loci that cause rare Mendelian disorders. This screen identified mutations in a gene called ANKLE2 that caused severe microcephaly as well as significant cognitive and neurological defects. Mutations in the Drosophila counterpart also lead to neuronal loss and smaller brains. ANKLE2 has been implicated to function in nuclear envelope formation during mitosis in C. elegans. However, it is unclear whether this function is conserved or how the loss of this gene causes microcephaly phenotypes in flies and men. The goal of this project is to understand how ANKLE2 and its interacting partners cause microcephaly using a genetic model system and to determine how this protein contributes to the development of the nervous system. Using Drosophila as a model system, the function of ANKLE2 in the nervous system will be determined.
Mutations in ANKLE2 are associated with microcephaly, a neurodevelopment disorder in which patients have decreased brain volumes. However, the function of ANKLE2 in neurodevelopment or disease is unknown. Using a genetic model system, this study will illuminate the function of ANKLE2 in the nervous system.
| Malmanche, Nicolas; Dourlen, Pierre; Gistelinck, Marc et al. (2017) Developmental Expression of 4-Repeat-Tau Induces Neuronal Aneuploidy in Drosophila Tauopathy Models. Sci Rep 7:40764 |
