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.
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.
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.
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).
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.)
Thank you for submitting a comment on this article. It will be reviewed by JAMA Psychiatry editors. You will be notified when your comment has been published. Comments should not exceed 500 words of text and 10 references.
Do not submit personal medical questions or information that could identify a specific patient, questions about a particular case, or general inquiries to an author. Only content that has not been published, posted, or submitted elsewhere should be submitted. By submitting this Comment, you and any coauthors transfer copyright to the journal if your Comment is posted.
* = Required Field
Disclosure of Any Conflicts of Interest*
Indicate all relevant conflicts of interest of each author below, including all relevant financial interests, activities, and relationships within the past 3 years including, but not limited to, employment, affiliation, grants or funding, consultancies, honoraria or payment, speakers’ bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. If all authors have none, check "No potential conflicts or relevant financial interests" in the box below. Please also indicate any funding received in support of this work. The information will be posted with your response.
Some tools below are only available to our subscribers or users with an online account.
Download citation file:
Web of Science® Times Cited: 56
Customize your page view by dragging & repositioning the boxes below.
More Listings atJAMACareerCenter.com >
Users' Guides to the Medical Literature
Sequencing the human genomeidentifying the entire sequence of base pairs in the 25 ...
All results at
Enter your username and email address. We'll send you a link to reset your password.
Enter your username and email address. We'll send instructions on how to reset your password to the email address we have on record.
Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.