An Unstable Trinucleotide-Repeat Region on Chromosome 13 Implicated in Spinocerebellar Ataxia: A Common Expansion Locus

Abstract

Larger CAG/CTG trinucleotide-repeat tracts in individuals affected with schizophrenia (SCZ) and bipolar affective disorder (BPAD) in comparison with control individuals have previously been reported, implying a possible etiological role for trinucleotide repeats in these diseases. Two unstable CAG/CTG repeats, SEF2-1B and ERDA1, have recently been cloned, and studies indicate that the majority of individuals with large repeats as detected by repeat-expansion detection (RED) have large repeat alleles at these loci. These repeats do not show association of large alleles with either BPAD or SCZ. Using RED, we have identified a BPAD individual with a very large CAG/CTG repeat 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 ( approximately 1,800 bp) in this patient. The repeat region localizes to chromosome 13q21, within 1.2 cM of fragile site FRA13C. Repeat alleles in our sample were unstable in 13 (5.6%) of 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 alleles were also detected for Centre d'Etude Polymorphisme Humaine (CEPH) reference family 1334. This triplet expansion has recently been reported to be the cause of spinocerebellar ataxia type 8 (SCA8); however, none of our large alleles above the disease threshold occurred in individuals either affected by SCA or with known family history of SCA. The high frequency of large alleles at this locus is inconsistent with the much rarer occurrence of SCA8. Thus, it seems unlikely that expansion alone causes SCA8; other genetic mechanisms may be necessary to explain SCA8 etiology.

Targeted Deletion of a SingleSca8Ataxia Locus Allele in Mice Causes Abnormal Gait, Progressive Loss of Motor Coordination, and Purkinje Cell Dendritic Deficits

“…For instance, an expanded CTG tract could have a direct negative impact on KLHL1 expression through interference with essential KLHL1 promoter elements. This direct mechanism, however, would not easily explain the incomplete penetrance of the SCA8 mutation or the observation that extremely large SCA8 repeat expansions do not appear to cause disease (Juvonen et al, 2000(Juvonen et al, , 2005Vincent et al, 2000;Sobrido et al, 2001;Corral et al, 2005). For this reason, we currently believe that mechanisms that require that the expansion be encoded in a transcript are more likely to be correct, because this provides a plausible explanation for the reduced penetrance associated with the SCA8 expansions (e.g., very large repeats may not be transcribed or spliced efficiently and would therefore not generate pathogenic RNA molecules).…”

Schizophrenia and genetics: New insights

“…For example, large unstable nucleotide repeats have been found to be responsible for several neuropsychiatric disorders. Large repeats do not appear to be involved in schizophrenia [53], although smaller repeats or other genomic instabilities remain a possible etiology and source of new mutations. A mechanism that included a high rate of spontaneous mutations predisposing to schizophrenia would be consistent with the low rate of family history of schizophrenia usually found in individuals with the illness, and apparently "sporadic" schizophrenia [26].…”

Transglutaminase Activity as a Possible Molecular Mechanism in the Etiopathogenesis of Neurodegenerative Diseases

“…For example, several experimental findings reported that TG2 activity in vitro leads to the formation of soluble aggregates of a-synuclein [47] or polyQ proteins [48,49] . To date, as previously reported, at least ten human CAG-expansion diseases have been described (Table 2) [50][51][52][53][54][55][56][57][58][59] and in at least eight of them their neuropathology is caused by the expansion in the number of residues in the polyglutamine domain to a value beyond [35][36][37][38][39][40]. Remarkably, the mutated proteins have no obvious similarities except for the expanded polyglutamine domain.…”