An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: A common expansion lotus

Larger CAG/CTG trinucleotide-repeat tracts in individuals affected with sch izophrenia (SCZ) and bipolar affective disorder (BPAD) in comparison with c ontrol individuals have previously been reported, implying a possible etiol ogical role for trinucleotide repeats in these diseases. Two unstable CAG/C TG repeats, SEF2-1B and ERDA1, have recently been cloned, and studies indic ate that the majority of individuals with large repeats as detected by repe at-expansion detection (RED) hwe large repeat alleles at these loci. These repeats do not show association of large alleles with either BPAD or SCZ. U sing RED, we have identified a BPAD individual with a very large CAG/CTG re peat that is not due to expansion at SEF2-1B or ERDA1. From this individual 's DNA, we have cloned a highly polymorphic trinucleotide repeat consisting of (CTA)(n) (CTG)(n), which is very long (similar to 1,800 bp) in this pat ient. The repeat region localizes to chromosome 13q21, within 1.2 cM of fra gile site FRA13C. Repeat alleles in our sample were unstable in 13 (5.4%) o f 231 meioses. Large alleles (>100 repeats) were observed in 14 (1.25%) of 1,120 patients with psychosis, borderline personality disorder, or juvenile -onset depression and in 5 (.7%) of 710 healthy controls. Very large allele s were also detected for Centre d'Etude Polymorphisme Humaine (CEPH) refere nce family 1334. This triplet expansion has recently been reported to be th e cause of spinocerebellar ataxia type 8 (SCA8); however, none of our large alleles above the disease threshold occurred in individuals either affecte d by SCA or with known family history of SCA. The high frequency of large a lleles at this locus is inconsistent with the much rarer occurrence of SCA8 . Thus, it seems unlikely that expansion alone causes SCA8; other genetic m echanisms may be necessary to explain SCA8 etiology.