Identification of ATP8A2 gene mutation in a consaguineous family segregating cerebellar atrophy and quadrupedal gait
Author
Onat, Onur Emre
Advisor
Özçelik, Tayfun
Date
2012Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
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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.