Long repeat tracts atSCA8 in major psychosis

Abstract

Expansion at a recently identified unstable trinucleotide repeat on chromosome 13q21 has been reported as the molecular cause for spinocerebellar ataxia type 8 (SCA8). The trinucleotide repeat, which consists of a [CTA]n repeat and adjacent [CTG]n repeat, was reported to have a pathogenic range of 107-127 CTG repeats (or 110-130 combined CTA and CTG repeats) in a large ataxia kindred. This repeat region was also cloned by our group from a bipolar affective disorder (BPAD) patient, who has approximately 600 combined repeats, and large alleles (>100 repeats) were reported to be present in 0.7% of controls and 1.5% of major psychosis patients (n = 710 and n = 1,120, respectively). We have followed up these findings by screening three new samples of BPAD and schizophrenia (SCZ) patients and controls, including 272 individuals from 14 BPAD families from Sweden, 130 individuals from 32 SCZ and BPAD families/trios from the Azores Islands, and 206 SCZ individuals from the United Kingdom and Ireland, and 219 matched controls. We found large repeat alleles above the SCA8 pathogenic range in individuals from 3 of 32 Azorean pedigrees and in 1 of 206 SCZ individuals from the United Kingdom, and repeat alleles within the SCA8 pathogenic range in 1 of 14 Swedish families. Although the rarity of major psychosis patients carrying the SCA8 expansion mutation would require a much larger sample size to reach statistical significance, these results support the previously reported observation of increased occurrence of large repeats at SCA8 in major psychosis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:873-876, 2000.

Analysis of SCA8 and SCA12 loci in 134 Italian ataxic patients negative for SCA1-3, 6 and 7 CAG expansions

“…Phenotype differences between subjects carrying an expansion could be related to a reduced penetrance of the SCA8 mutation, as previously suggested [1,7]. In fact the penetrance and the expressivity of expanded SCA8 alleles appear to be complex: very large alleles (> 170 repeats) have been occasionally found in healthy subjects, and thought to be non-pathogenic [1,7].A higher rate of large alleles (> 100 repeats) than in controls was found in patients with major psychosis [24,25]. On the other hand the asymptomatic father, carrying 136 SCA8 repeats, of an affected boy carrying a 95 triplets expansion, showed mild cerebellar atrophy an MRI [6].…”

“…The two families are not related and do not share a common SCA8 haplotype. More than 99 % of normal SCA8 alleles reported so far range from 2 to 37 combined (CTA) 1-21 +(CTG) n triplets, but the definition of a pathological threshold is quite problematic, since a small proportion of controls carry 40-91 triplets, and occasionally larger alleles containing from 91 to > 900 triplets have been described in healthy subjects [8,19,[24][25][26]. This latter group also comprises expansions overlapping the 110-130 triplets described by Koob et al [8] in the first SCA8 family (MN-A), suggesting a reduced penetrance in this disease.…”

Comparison of microarray-based mRNA profiling technologies for identification of psychiatric disease and drug signatures

“…Mouse and cell models of the disease show defects in short-term potentiation and neuronal cell death (Yoo et al, 2003;Zander et al, 2001). Of interest, several laboratories have suggested and provided some evidence that triplet nucleotide expansion in other spinal cerebellar ataxia genes may be associated with neuropsychiatric disorders including psychosis, bipolar disorder, and schizophrenia (Joo et al, 1999;Tashiro et al, 1999;Vincent et al, 2000).…”

Bidirectional expression of the SCA8 expansion mutation: One mutation, two genes

“…In addition to finding SCA8 expansions in controls, SCA8 expansions have also been reported in individuals with positive gene tests for SCA1 (22), SCA6 (23) and Friedreich's ataxia (24) as well as in patients with psychiatric diseases (21,25), Alzheimer's disease and Parkinson's disease (23,24). While it is clear that SCA8 expansions are found at higher frequencies among ataxia patients with no other identified genetic cause than in controls (17), SCA8 expansions were not found at higher frequencies in a large cohort of psychiatric patients (21,25).…”

“…While it is clear that SCA8 expansions are found at higher frequencies among ataxia patients with no other identified genetic cause than in controls (17), SCA8 expansions were not found at higher frequencies in a large cohort of psychiatric patients (21,25). It is not yet clear if reported cases of SCA8 expansions in ataxia patients with other mutations or in patients with other neurological conditions are functionally significant or simply occur by chance given the relatively high frequency of SCA8 expansions in controls.…”