Trinucleotide Repeat Expansion and Neuropsychiatric Disease

Abstract

Trinucleotide, or triplet, repeats consist of 3 nucleotides consecutively repeated (e.g., CCG CCG CCG CCG CCG) within a region of DNA, a not uncommon motif in the genome of humans and other species. In 1991, a new type of genetic mutation was discovered, known as a dynamic or expansion mutation, in which the number of triplets in a repeat increases and the length becomes unstable. During the past decade, nearly 20 diseases-including Huntington disease, 2 forms of the fragile X syndrome, and myotonic dystrophy-caused by trinucleotide repeat expansions have been identified. The unstable nature of the expanded repeat leads to remarkable patterns of inheritance in these diseases, distinctly at odds with traditional notions of mendelian genetics. We review the clinical and genetic features of these disorders, with a particular emphasis on their psychiatric manifestations. We also critically examine the hypothesis that expansion mutations may have an etiologic role in psychiatric diseases such as bipolar disorder, schizophrenia, and autism.

A novel CpG-associated brain-expressed candidate gene for chromosome 18q-linked bipolar disorder

“…12 In further studies we refined the linkage region at 18q21-q22, identified by De Bruyn et al in a multiplex Belgian BP family, 6 to an 8.9 cM region between D18S68 and D18S979 at 18q21-q22 and constructed a physical map using yeast artificial chromosomes (YACs). 13 Our candidate region at chromosome 18q21-q22 identified in the Belgian study overlaps with that reported by Stine et al 2 Several studies have described anticipation in families transmitting BP disorder, [14][15][16] suggesting the involvement of trinucleotide repeat expansions (TREs). Support for the involvement of CAG/CTG repeat expansions in BP disorder was obtained by the use of the repeat expansion detection (RED) method.…”

“…In-depth analysis showed that three (CCG3, GenBank accession number AF480432; CCG4, GenBank accession number AF480433; and CCG6, GenBank accession number AF480434) of the seven end sequences had a high CG (70-80%) and CpG (15)(16)(17)(18)(19)(20) CpGs in 200 bp) content. Primer pairs flanking these potential CpG island were used to determine their position on the YAC contig ( Figure 1).…”

“…28 Together these data make it unlikely that CAG/CTG repeats would explain the anticipation in BP families and the association in BP cases/control populations. 26 Considering that a number of diseases caused by an expansion of a CCG/CGG repeat show anticipation (reviewed by Margolis et al 16 ), we originally aimed at identifying CCG/CGG repeats from within the 18q21-q22 region using a variant of the CAG repeat YAC fragmentation method. Instead, the method was more efficient in identifying CpG islands than CCG/CGG repeats.…”

European combined analysis of the CTG18.1 and the ERDA1 CAG/CTG repeats in bipolar disorder

“…6 A number of groups have tested this hypothesis using the Repeat Expansion Detection (RED) method, which identifies the size of the largest trinucleotide repeat present in the genome of an individual. 7 Of eight independent studies four reported association.…”

Cloning and Characterization of Expanded CAG-Repeat Containing Sequence(s): Identification of Candidate Breast Cancer Predisposition (Gene(s)

“…The effect depends on the location of the repeats relative to the gene and the type of repeats (for review see Sanjeeva et. al., 1997, Margolis et al, 1999, Vincent et al, 2000. The molecular consequences that result from trinucleotide repeat expansions and the mechanism by which they lead to pathology may be quite diverse.…”