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Trinucleotide Repeat Expansion and Neuropsychiatric Disease

Russell L. Margolis, MD; Melvin G. McInnis, MD; Adam Rosenblatt, MD; Christopher A. Ross, MD, PhD
Arch Gen Psychiatry. 1999;56(11):1019-1031. doi:10.1001/archpsyc.56.11.1019.
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Trinucleotide, or triplet, repeats consist of 3 nucleotides consecutively repeated (eg, 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.

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Figure 1.

Molecular pathogenesis of Huntington disease (HD) and the fragile X (FraX) syndrome. Left, The effect of a CAG repeat expansion in the Htt gene. Within the nucleus (yellow), genes with either a normal CAG repeat or an expanded CAG repeat are transcribed into messenger RNA (mRNA), with normal excision of introns and splicing together of exons. Outside the nucleus, mRNA with either a normal or a long CAG repeat is translated into protein. The CAG repeat itself, located within a protein coding region (blue), is translated into a stretch of the amino acid glutamine (Q). The mutant protein, containing an excessively long polyglutamine (polyQ) repeat, takes on an abnormal conformation that confers new and toxic properties to the protein. Right, The effect of an expansion of the CGG repeat in the FraX mental retardation type 1 (FMR1) gene. In FMR1 with a normal-length repeat, the gene is transcribed into mRNA, and the mRNA is translated into protein. The CGG repeat is located outside the protein coding region and, hence, is not translated into an amino acid repeat. In FMR1 with an expanded CGG repeat, the expansion prevents gene transcription into mRNA and therefore no protein is synthesized. Disease arises from a lack of the protein.

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Figure 2.

Genetic locations of repeat expansions. Repeat expansions that cause disease have been detected in flanking and intronic regions, transcribed but untranslated regions, and protein coding regions (orange). Expansions within protein coding regions tend to be smaller than those in other genic regions. EPM1 indicates progressive myoclonic epilepsy type 1; SCA, spinocerebellar ataxia; OPMD, oculopharyngeal muscular dystrophy; MED, multiple epiphyseal dysplasia; HD, Huntington disease; DRPLA, dentatorubral-pallidoluysian atrophy; and SBMA, spinal and bulbar muscular atrophy.

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Figure 3.

The molecular basis for anticipation in repeat expansion diseases. Data are from the Baltimore (Md) Huntington's Disease Center. Left, Increase in repeat length with paternal transmission of Huntington disease (HD). Points above the diagonal line represent cases in which the repeat length increased during transmission from father to child (N = 84 pairs, mean ± SD increase of repeat length = 4.2 ± 0.8 triplets). Right, Correlation of repeat length with age at onset in HD. As repeat length increases, age at onset of disease decreases (N = 480, r2 = 0.57).

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Figure 4.

Anticipation in Huntington disease (HD) (left) and affective disorder (right). The age at which affected parents and their affected offspring first manifest disease symptoms is depicted as a survival curve. In both HD and affective disorder, the younger generation is affected at a substantially earlier age than their parents. (Subjects with affective disorder are from the Johns Hopkins Bipolar Project [Baltimore, Md]: parents, N = 36; offspring, N = 97. Subjects with HD are from the Baltimore Huntington's Disease Center: parents, N = 61; offspring, N = 82.)

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