Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion

PubMedID: 22892528Cerebellar 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.National Institutes of Health: RC02 NS070477 Yale University National Council for Scientific Research: 108S355, TUBITAK-SBAG 108S036We are grateful to Dr Mary-Claire King for innumerable discussions and suggestions. We also thank the members of Family C for cooperation in this study. This work was supported by the Scientific and Technological Research Council of Turkey (TUBITAK-SBAG 108S036 and 108S355) and Turkish Academy of Sciences (TUBA research support) to TO; Yale Program on Neurogenetics, the Yale Center for Human Genetics and Genomics and National Institutes of Health grants RC02 NS070477 to MG