Noncoding Triplet Repeat Disorders

The noncoding triplet repeat diseases typically have large and variable repeat expansions that result in multiple tissue dysfunction or degeneration. The triplet repeat sequences vary in this subclass (CGG, GCC, GAA, CTG, and CAG). It is clear that the particular triplet sequence and its location with respect to a gene are important defining factors in dictating the unique mechanism of pathogenesis for each disease. The pathogenic mechanism also varies from disease to disease depending on the consequences of the lost function of the respective proteins or in some cases acquired function of a toxic transcript.

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 (FMRi) 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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Pregnancy And Childbirth

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