Cerebellar Ataxia, Cayman Type

A number sign (#) is used with this entry because of evidence that Cayman cerebellar ataxia (ATCAY) is caused by homozygous mutation in the ATCAY gene (608179), which encodes the neuron-restricted protein caytaxin, on chromosome 19p13.

Clinical Features

Autosomal recessive Cayman cerebellar ataxia, identified by Johnson et al. (1978) in a population isolate on Grand Cayman Island, is characterized by marked psychomotor retardation and prominent nonprogressive cerebellar dysfunction including nystagmus, intention tremor, dysarthria, and wide-based ataxic gait. Hypotonia is present from early childhood; retinal abnormalities are absent.

Mapping

Nystuen et al. (1996) identified 19 affected individuals from this isolate. Based on the assumption of identity by descent (IBD) at the disease locus in affected individuals, they used a DNA pooling strategy to perform a genomewide screen of polymorphic markers to search for a genomic interval in linkage disequilibrium with the disease. Two affected pools (one contained DNA from all affected individuals, the other contained DNA from the 10 most closely related affected individuals) and a pool of DNA from unaffected sibs and parents of affected individuals were screened with 300 STRPs (short tandem repeat polymorphisms) (Sheffield et al., 1995). A single chromosome 19 marker, GATA66B01, was found to show a significantly different allele pattern consistent with IBD. Through analysis of additional proximal and distal markers on chromosome 19p13.3, Nystuen et al. (1996) mapped the Cayman cerebellar ataxia gene to a 9-cM region between the flanking markers D19S424 and GATA66B01.

Molecular Genetics

In individuals with Cayman ataxia, Bomar et al. (2003) found homozygosity for 2 sequence variants in the ATCAY gene: a ser301-to-arg (S301R) substitution and a splice site mutation in intron 9 (608179.0001). Both mutations completely segregated with the disorder and with carrier status in over 40 family members who were genotyped blindly. Neither mutation was found in any of more than 1,000 chromosomes from several different ethnic groups.

Animal Model

Comparative mapping suggested that the mouse mutation 'jittery,' which maps to the homologous region on mouse chromosome 10 (Kapfhamer et al., 1996), might be homologous to ATCAY. Because many spontaneous mouse mutations are caused by deletions or insertions, Bomar et al. (2003) screened all genes from the critical region of mouse chromosome 10 by Southern blot hybridization. One probe for an unknown predicted gene showed DNA changes in both jittery and the allelic 'hesitant' mouse. In silico restriction mapping predicted the locations of the mutations as exon 4 and intron 1, respectively, and genomic PCRs showed larger products in each case. The insertion in exon 4 of jittery was the first mouse mutation caused by an Alu-related mutagenesis, which is common in humans (Kazazian and Moran, 1998).