Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion.
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.
Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey.
Onur Emre
OE
Onat
Suleyman
S
Gulsuner
Kaya
K
Bilguvar
Ayse
A
Nazli Basak
Haluk
H
Topaloglu
Meliha
M
Tan
Uner
U
Tan
Murat
M
Gunel
Tayfun
T
Ozcelik
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000595:Amino Acid Sequence; D001284:Atrophy / Q000235:genetics*; D001483:Base Sequence; D001921:Brain / Q000502:physiology; D002524:Cerebellar Ataxia / Q000235:genetics; D002531:Cerebellum / Q000473:pathology*; D002882:Chromosomes, Human, Pair 13; D005260:Female; D005684:Gait / Q000235:genetics; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008124:Locomotion; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D049294:Phospholipid Transfer Proteins / Q000235:genetics*
D049294:Phospholipid Transfer Proteins; D000251:Adenosine Triphosphatases; C545445:ATP8A2 protein, human