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

被引:102
作者
Onat, Onur Emre [1 ]
Gulsuner, Suleyman [1 ]
Bilguvar, Kaya [2 ,3 ,4 ,5 ]
Basak, Ayse Nazli [6 ]
Topaloglu, Haluk [7 ]
Tan, Meliha [8 ]
Tan, Uner [9 ]
Gunel, Murat [2 ,3 ,4 ,5 ]
Ozcelik, Tayfun [1 ,10 ]
机构
[1] Bilkent Univ, Dept Mol Biol & Genet, Fac Sci, TR-06800 Ankara, Turkey
[2] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT USA
[3] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA
[4] Yale Univ, Sch Med, Dept Genet, Ctr Human Genet & Genom, New Haven, CT 06510 USA
[5] Yale Univ, Sch Med, Program Neurogenet, New Haven, CT USA
[6] Bogazici Univ, Dept Mol Biol & Genet, NDAL Lab, Sch Arts & Sci, Istanbul, Turkey
[7] Hacettepe Univ, Fac Med, Dept Pediat Neurol, Ihsan Dogramaci Childrens Hosp, TR-06100 Ankara, Turkey
[8] Baskent Univ, Dept Neurol, Fac Med, TR-06490 Ankara, Turkey
[9] Cukurova Univ, Dept Physiol, Fac Med, Adana, Turkey
[10] Bilkent Univ, Inst Mat Sci & Nanotechnol UNAM, Ankara, Turkey
基金
美国国家卫生研究院;
关键词
ATP8A2; cerebellar hypoplasia; targeted next-generation sequencing; quadrupedal locomotion; CAMRQ; GENE; HYPOPLASIA; SEQUENCE; VLDLR; RESOURCES; EVOLUTION; DELETION; HUMANS; MODEL;
D O I
10.1038/ejhg.2012.170
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. European Journal of Human Genetics (2013) 21, 281-285; doi:10.1038/ejhg.2012.170; published online 15 August 2012
引用
收藏
页码:281 / 285
页数:5
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