CAG repeat expansions

Ikeuchi, T., Takano, H., Koide, R. et al Spinocerebellar ataxia type 6 CAG repeat expansion in alA voltage-dependent calcium channel gene and clinical variations in Japanese population. Ann. Neurol 42 879-884,1997. 

David, G., Abbas, N., Stevanin, G. etal Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion. Nat. Genet. 17 65-70,1997. 

C12. Choong, C. S., Kemppainen, J. A., Zhou, Z. X., and Wilson, E. M., Reduced androgen receptor gene expression with first exon CAG repeat expansion. Mol. Endocrinol. 10, 1527-1535 (1996). 

Vnencak-Jones CL. Fluorescence PCR and GeneScan analysis for the detection of CAG repeat expansions associated with Huntington s disease. Methods Molec Biol 2003 217 101-10. 

Koide, R., Ikeuchi, T., Onodera, O. et al. Unstable expansion of CAG repeat in hereditary dentatorubralpallidoluysian atrophy (DRPLA). Nat. Genet. 6 9-13,1994. 

Ikeuchi, T., Koide, R., Tanaka, H. et al. Dentatorubral pallidoluysian atrophy clinical features are closely related to unstable expansions of trinucleotide (CAG) repeat. Ann. Neurol. 37 769-775,1995. 

Huntington s disease (HD) is caused by mutations in a gene called Huntingtin. The disease is caused by abnormal expansion of CAG repeats, which encode long stretches of glutamine (polyglutamine). In addition to HD, there are several other known polyglutamine diseases such as spinocerebellar ataxia, and spinal and bulbar muscular atrophy. " ... 

Fortune MT, Kennedy JL, Vincent JB. 2003. Anticipation and CAG CTG repeat expansion in schizophrenia and bipolar affective disorder. Curr Psychiatry Rep 5(2) 145-154. 

From Cummings and Zoghbi (2000) updated to include Spinocerebellar atajda type 17 and new information on CAG repeat size in some of the diseases. SubceUular location of brain protein aggregates typical of the Q -expansion diseases are as follows n, nuclear c, cytosolic. 

The disease is caused by a CAG expansion in the SCA6 gene at chromosome 19pl3, which codes for the aia-voltage-dependent calcium channel subunit (Zhuchenko et al., 1997). Six isoforms of this protein have been described. The CAG repeat is within the open reading frame and is predicted to encode Qn domains in... 

Huntingtin (htt) a causative gene of Huntington s Disease (HD), with its N-terminal CAG trinucleotide repeat expansion correlated with the onset of the disease. Predicted to function as a scaffolding molecule for multiple transporting/transcrip-tional molecules in cytoplasm and nucleus. Inclusion of htt and/or its N-terminal polyglutamine tract have been proposed as a potential mechanism of neurodegeneration in HD. 

Figure 40-4 Schematic representation of the polygiutamine-encoding CAG repeat in exon 1 of the HD gene and associated alleles. A CAG-repeat number <27 is considered normal. CAG-repeat numbers of 28 to 35 are mutable" and although they are not associated with an abnormal phenotype, these alleles are prone to meiotic expansion to an HD allele. CAG repeats of 36 to 39 are considered HD alleles but with reduced penetrance, indicating that both unaffected and affected patients have been reported with alleles of this size, CAG repeats >40 are associated with HD with complete penetrance.

Kremer B, Almqvist E, TheHmann J, Spence N, Tele-nius H, Goldberg YP, et al. Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes. Am J Hum Genet 1995 57 343-50. 

Subsequently, small expansions of a polymorphic CAG repeat in the same gene were identified in some ataxic patients with a condition since designated SCA6, a dominantly inherited progressive cerebellar ataxia clinically indistinguishable from other dominant ataxic syndromes (Zhuchenko et al 1997). Some patients experience fluctuating symptoms, similar to episodic ataxia. 

Abnormal numbers of CAG repeats in the NTD also are associated with certain diseases. The CAG repeats encode for a polyglutamine tract that begins at amino acid 58 in AR, and normally includes between 11 and 33 residues. Spinobulbar muscular atrophy (Kennedy s disease) is caused by expansion of these repeats leading to lengthening ofthe polyglutamine tract [29]. Likewise, some studies suggest that shorter... 

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