İnsanda el-ayak üzerinde yürüme: WD repeat domain 81 (WDR81) geni?nin tanımlanması ve kısmi karakterizasyonu

Identification of disease genes responsible for cerebellar phenotypes provides mechanistic insights into the development of cerebellum. Neural pathways involved in bipedal gait in humans is not completely understood. Cerebellar ataxia, mental retardation, and disequilibrium syndrome (CAMRQ) is a rare neurodevelopmental disorder accompanied by quadrupedal gait, dysarthric speech and cerebellar hypoplasia. A large consanguineous family exhibiting this rare disorder was investigated in this study. Disease locus was mapped to a 7.1 Mb region on chromosome 17p by genetic analysis. Targeted capture and massively parallel DNA sequencing using the DNA of three affected and two carrier individuals enabled the identification of a novel variant, p.P856L, in a predicted transcript of WD repeat domain 81 gene (WDR81). Several exclusion filters including segregation analysis, identification of rare polymorphisms, extended pedigree screen and bioinformatics evaluation was performed. Expression analysis revealed highest levels of transcripts in cerebellum and corpus callosum. In mouse brain Wdr81 RNA was observed in cerebellum, especially in Purkinje cell layer. The major structural abnormalities of the patients were atrophy of superior, middle and inferior cerebellar peduncles and corpus callosum. These findings are compatible with the expression pattern of the gene. Analysis of the developing mouse brain revealed that, the expression pattern of the gene was correlated with those involved in neuronal differentiation. This study was one of the first examples of the utility of next generation sequencing in discovery of genes associated with Mendelian phenotypes.