Identification of ATP8A2 gene mutation in a consaguineous family segregating cerebellar atrophy and quadrupedal gait

Simple item page
buir.advisorÖzçelik, Tayfun
dc.contributor.authorOnat, Onur Emre
dc.date.accessioned2016-01-08T18:20:31Z
dc.date.available2016-01-08T18:20:31Z
dc.date.issued2012
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.descriptionAnkara : The Department of Molecular Biology and Genetics and the Graduate School of Engineering and Science of Bilkent University, 2012.en_US
dc.descriptionThesis (Ph. D.) -- Bilkent University, 2012.en_US
dc.descriptionIncludes bibliographical references leaves 138-153.en_US
dc.description.abstractCerebellar ataxia, mental retardation, and dysequilibrium syndrome is a rare and heterogeneous neurodevelopmental disorder characterized by cerebellar atrophy, dysarthric speech, and quadrupedal locomotion. Here, a consanguineous family with four affected individuals which suggest an autosomal recessive inheritance was investigated. Homozygosity mapping analysis using high-resolution genotyping arrays in two affected individuals revealed four shared homozygous regions on 13q12, 19p13.3, 19q13.2, and 20q12. Target enrichment and next-generation sequencing of these regions in an affected individual was uncovered 11 novel protein altering variants which were filtered against dbSNP132 and 1000 genomes databases. Further population filtering using personal genome databases and previous exome sequencing datasets, segregation analysis, geographically-matched population screening, and prediction approaches revealed a novel missense mutation, p.I376M, in ATP8A2 segregated with the phenotype in the family. The mutation resides in a highly conserved C-terminal transmembrane region of E1-E2 ATPase domain. ATP8A2 is mainly expressed in brain, in particular with the highest levels at cerebellum which is a crucial organ for motor coordination. Mice deficient with Atp8a2 revealed impaired axonal transport in the motor neurons associated with severe cerebellar ataxia and body tremors. Recently, an unrelated individual with a de novo t(10;13) balanced translocation whose one of the ATP8A2 allele was disrupted has been identified. This patient shares similar neurological phenotypes including severe mental retardation and hypotonia. These findings suggest a role for ATP8A2 in the neurodevelopment, especially in the development of cerebro-cerebellar structures required for posture and gait in humans.en_US
dc.description.degreePh.D.en_US
dc.description.statementofresponsibilityOnat, Onur Emreen_US
dc.format.extentxxiv, 181 leaves, illustrations, graphsen_US
dc.identifier.urihttp://hdl.handle.net/11693/15555
dc.language.isoEnglishen_US
dc.publisherBilkent Universityen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectQuadrupedal locomotionen_US
dc.subjectCAMRQen_US
dc.subjectCerebellar atrophyen_US
dc.subjectNext-generation sequencingen_US
dc.subjectATP8A2en_US
dc.subject.lccWL390 .O53 2012en_US
dc.subject.lcshGait disorders Genetic aspects.en_US
dc.subject.lcshCerebral diseases.en_US
dc.subject.lcshHuman locomotion.en_US
dc.titleIdentification of ATP8A2 gene mutation in a consaguineous family segregating cerebellar atrophy and quadrupedal gaiten_US
dc.typeThesisen_US

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
0006284.pdf
Size:
7.71 MB
Format:
Adobe Portable Document Format
Download

Collections

Dept. of Molecular Biology and Genetics - Ph.D. / Sc.D.