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      • Dept. of Molecular Biology and Genetics - Ph.D. / Sc.D.
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      Identification of ATP8A2 gene mutation in a consaguineous family segregating cerebellar atrophy and quadrupedal gait

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      Author
      Onat, Onur Emre
      Advisor
      Özçelik, Tayfun
      Date
      2012
      Publisher
      Bilkent University
      Language
      English
      Type
      Thesis
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      Abstract
      Cerebellar 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.
      Keywords
      Quadrupedal locomotion
      CAMRQ
      Cerebellar atrophy
      Next-generation sequencing
      ATP8A2
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      http://hdl.handle.net/11693/15555
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