Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse

被引:98
作者
Bomar, JM
Benke, PJ
Slattery, EL
Puttagunta, R
Taylor, LP
Seong, E
Nystuen, A
Chen, WD
Albin, RL
Patel, PD
Kittles, RA
Sheffield, VC
Burmeister, M
机构
[1] Univ Michigan, Mental Hlth Res Inst, Ann Arbor, MI 48109 USA
[2] Univ Miami, Dept Pediat, Miami, FL 33152 USA
[3] Univ Michigan, Neurosci Program, Ann Arbor, MI 48109 USA
[4] Univ Iowa, Howard Hughes Med Inst, Iowa City, IA 52242 USA
[5] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA
[6] Univ Iowa, Dept Human Genet, Iowa City, IA 52242 USA
[7] Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA
[8] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA
[9] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA
[10] Univ Michigan, Dept Neurol, Ann Arbor, MI 48109 USA
[11] Univ Michigan, Vet Assoc Med Ctr, Ann Arbor, MI 48109 USA
关键词
D O I
10.1038/ng1255
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Cayman ataxia is a recessive congenital ataxia restricted to one area of Grand Cayman Island(1,2). Comparative mapping suggested that the locus on 19p13.3 associated with Cayman ataxia might be homologous to the locus on mouse chromosome 10 associated with the recessive ataxic mouse mutant jittery. Screening genes in the region of overlap identified mutations in a novel predicted gene in three mouse jittery alleles, including the first mouse mutation caused by an Alu-related (B1 element) insertion. We found two mutations exclusively in all individuals with Cayman ataxia. The gene ATCAY or Atcay encodes a neuron-restricted protein called caytaxin. Caytaxin contains a CRAL- TRIO motif common to proteins that bind small lipophilic molecules. Mutations in another protein containing a CRAL-TRIO domain, alpha-tocopherol transfer protein ( TTPA), cause a vitamin E responsive ataxia. Three-dimensional protein structural modeling predicts that the caytaxin ligand is more polar than vitamin E. Identification of the caytaxin ligand may help develop a therapy for Cayman ataxia.
引用
收藏
页码:264 / 269
页数:6
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