Browsing by Subject "ATP8A2"

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Open Access
Identification of ATP8A2 gene mutation in a consaguineous family segregating cerebellar atrophy and quadrupedal gait
(2012) Onat, Onur Emre
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.
Open Access
Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion
(Nature Publishing Group, 2013) Onat, O. E.; Gulsuner, S.; Bilguvar, K.; Basak, A. N.; Topaloglu, H.; Tan, M.; Tan, U.; Gunel, M.; Ozcelik, T.
Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebro-cerebellar structures required for posture and gait in humans. © 2013 Macmillan Publishers Limited All rights reserved.