Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse.
Cayman ataxia is a recessive congenital ataxia restricted to one area of Grand Cayman Island. 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.
Bomar
Jamee M
JM
Mental Health Research Institute, 205 Zina Pitcher Place, University of Michigan, Ann Arbor, Michigan 48109-0720, USA.
Benke
Paul J
PJ
Slattery
Eric L
EL
Puttagunta
Radhika
R
Taylor
Larry P
LP
Seong
Eunju
E
Nystuen
Arne
A
Chen
Weidong
W
Albin
Roger L
RL
Patel
Paresh D
PD
Kittles
Rick A
RA
Sheffield
Val C
VC
Burmeister
Margit
M
D000595:Amino Acid Sequence; D000818:Animals; D001259:Ataxia / Q000235:genetics*; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D004195:Disease Models, Animal; D004421:Dystonia / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D017386:Sequence Homology, Amino Acid