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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS092270-03
Application #
9249119
Study Section
Special Emphasis Panel (ZRG1-F03A-N (20)L)
Program Officer
Riddle, Robert D
Project Start
2015-04-01
Project End
2017-06-30
Budget Start
2017-04-01
Budget End
2017-06-30
Support Year
3
Fiscal Year
2017
Total Cost
$16,037
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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