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

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  • A Corrigendum to this article was published on 01 May 2005

Abstract

Cayman ataxia is a recessive congenital ataxia restricted to one area of Grand Cayman Island1,2. 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.

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Figure 1: The critical regions of Cayman ataxia and jittery overlap.
Figure 2: Mutations in Atcay in three jittery alleles.
Figure 3: Two mutations found in individuals with Cayman ataxia.
Figure 4: Atcay is a highly expressed neuron-specific gene.
Figure 5: Alignment of predicted protein sequences with related genes across species.
Figure 6: Comparison of the predicted structure of caytaxin with that of TTPA.

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Acknowledgements

We thank the subjects and their family members on the Cayman Islands for their participation; K. Portman, D. Kapfhamer, J. Lee, C. Pontrello, C. Searby and D. Sufalko for technical assistance; M. Owen for the British control samples; P. Nishina and C. Avery for the sidewinder mutant mice; M. Reese for help interpreting splice site predicting program results; D. Jenne, T. Wilkie and A. Olsen for communication of unpublished results; N. Gilbert and J. Moran for discussion of B1-element insertions; D. Speert, C. Neal and A. Seasholtz for help with in situ hybridization; and the Morphology Core of the Center for Organogenesis of the University of Michigan for providing slides of mouse embryos. We thank the National Institute of Neurological Disorders and Stroke (M.B.), the March of Dimes Birth Defect Foundation (M.B.) and the government of the Cayman Islands (P.J.B.) for funding. V.C.S. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Margit Burmeister.

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The regents of the University of Michigan have filed two provisional patent applications titled 'Ataxia-associated gene and protein'.

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Bomar, J., Benke, P., Slattery, E. et al. Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse. Nat Genet 35, 264–269 (2003) doi:10.1038/ng1255

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