Quadrupedal gait in humans : identification and partial characterization of a novel gene WD repeat domain 81 (WDR81)

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Author
Gülsüner, Süleyman İsmail
Advisor
Özçelik, Tayfun
Date
2011Publisher
Bilkent University
Language
English
Type
Thesis
Metadata
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http://hdl.handle.net/11693/15223Abstract
Identi cation 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 a ected and two carrier individuals enabled
the identi cation of a novel variant, p.P856L, in a predicted transcript of
WD repeat domain 81 gene (WDR81). Several exclusion lters including segregation
analysis, identi cation 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 ndings 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 di erentiation. This study was one of the rst examples of
the utility of next generation sequencing in discovery of genes associated with
Mendelian phenotypes.