Developmental Neurogenetic Disorders

Our lab has a long-standing commitment to gene discovery in neurodevelopmental disorders. To circumvent the challenges associated with genetic and phenotypic heterogeneity of neurodevelopmental disorders, we perform genetic analysis of consanguineous families (those that have recent shared ancestry), especially those with multiple affected individuals. This offers us a unique window for the identification of genes that cause inherited conditions. Over the years, we have established extremely important relationships with colleagues within the country and also internationally. We have an excellent collection of families recruited in Turkey, with varying degree of neurodevelopmental disorders including structural abnormalities (such as agyrias, pachygyrias, lissencephaly, microcephaly disorders), neurodegenerative disorders (ALS, HSP, parkinson’s, neuroaxonal dystrophy, Friedreich’s ataxia, etc), connectivity disorders (such as mental retardation, autism, epilepsy) skeletal dysplasias (involving growth, organisation development and maintenance of the skeleton).

Tracing shared ancestry in founder populations using novel whole-genome technologies such as homozygozity mapping (HM) and whole exome sequencing (WES) is a powerful approach to understand the genetic contributors to neurodevelopmental disorders. With this approach setting the stage for discovery, we first reported that WDR62 mutations cause cortical malformations (Bilgüvar K, Oztürk AK, et al. 2010). Since then, using the same approach, we have successfully identified other genes involved in cortical malformations: Laminin gamma 3 (Barak T, Kwan KY, et al. 2011; Radmanesh F, Caglayan AO., et al. 2013), NDE1 (Bakircioglu M, Carvalho OP., et al. 2011), UCHL1 (Bilguvar K, Tyagi NK, et al. 2013), Katanin B1 (Mishra-Gorur K, Çağlayan AO, et al., 2014), NGLY1 (Caglayan AO, Comu S, et al. 2015) and CLP1 (Schaffer AE, Eggens VR, et al. 2014).

The cache of candidate genes identified by extensive bioinformatics data and analysis is then routed into the wet lab, where we harness the power of various in vitro and in vivo model systems, cell biology, molecular biology and biochemistry tools to elucidate the functional effects of the mutations identified.

Studies aimed at elaborating the relevance of neuro-development related mutations necessitate the use of a wide range of in vitro and in vivo approaches. We use vertebrate model systems like Mouse and Zebrafish (Danio rerio) – both of which are established models for the analysis of genes involved in brain development and function. We have successfully used and continue to use traditional and conditional gene knockouts in mice to understand the role of identified genes. In addition, more recently, we are also exploiting the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) Type II system and using Zebrafish to model and study structural brain malformations caused by the candidate genes. Finally, given the largely conserved roles of key genes in brain development across various species, we continue to harness the power of Drosophila genetics to elucidate the functional roles of various candidate genes in causing cerebral malformations.

The use of animal models in the lab is intricately inter-woven with the use of tissue culture systems (primary and established cell cultures as well IPSC work), cell biological approaches using immunohistochemistry and in vivo imaging and finally molecular biology and biochemistry to dissect effects of mutations at a molecular level.