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Triplet Repeat Disease

Implicated In Diseases, Classification Of Triplet Repeat Disorders, Noncoding Triplet Repeat Disorders, Polyglutamine Diseases

Trinucleotide, or triplet repeats, consist of three consecutive nucleotides that are repeated within a region of DNA (for example, CCG CCG CCG CCG CCG). Expansion of a triplet repeat gene segment leads to increased disease severity and decreased age of onset in proportion to the degree of expansion. Repeats that are translated into protein alter the structure of the protein, conferring new functions. These are found in the genome of humans and many other species. All possible combinations of nucleotides are known to exist as triplet repeats, though some, including CGG and CAG, are more common than others. The repeats may be within genes or between genes. In genes, they may be in regions that specify proteins (coding regions called exons) or in noncoding regions (introns). If present within exons, they may be present in translated regions and hence encode a series of identical amino acids, or they may occur in regions not translated into protein. Triplet repeats are frequently found in genes that encode transcription factors and those involved in regulating development.

Fragile X Syndrome.

This disorder is caused by the expansion of a (CGG)n repeat in the 5′ untranslated region of the fragile X mental retardation (FMR1) gene. Normally there are about six to fifty-three repeats in this region. In the disease state there are more than 230 triplet repeats. This causes the transcriptional silencing of the gene, leading to loss of normal gene function. Some of the symptoms seen in this disorder include mental retardation, deformed features, and hyperactivity.

Myotonic Dystrophy (DM).

DM is a multisystem disorder with highly variable phenotypes and anticipation. Rigidity of muscles after contraction (tonic spasms), muscle weakness, and progressive muscle wasting characterize adult-onset DM. Developmental abnormalities, mental handicap, and respiratory distress are often evident in more severe forms. DM is caused by an expanded CTG triplet repeat in the 3′ untranslated region of the protein kinase gene DMPK. The CTG expansion may disrupt DMPK transcription, causing loss of function. CTG expansions may also cause loss of function in two genes flanking DMPK: the DM locus-associated home-odomain protein (DMAHP) and gene 59 (also known as DMWD). The CTG expanded transcript could also gain toxic function by interfering with normal processing of various RNAs. Congenital myotonic dystrophy occurs from birth in infants whose mothers have DM, often a case so mild it is never diagnosed. Due to anticipation, the child is much more severely affected than the mother.

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Medicine EncyclopediaGenetics in Medicine - Part 4