ABSTRACT
Instability and polymorphism at several CAG/CTG trinucleotide repeat loci have been associated with human genetic disorders. In an attempt to identify novel sites that may be possible loci for expansion of CAG/CTG repeats, we searched all human sequences in the EMBL nucleotide sequence database for (CAG)5 and (CTG)5 repeats. We have identified 121 human DNA sequences of known and unknown functions that contain stretches of five or more CAG or CTG repeats. Many repeat stretches were interrupted by variant triplets, a significant number of which differ from the repeat triplet only by a single base, suggesting that these evolved from the parent triplet by point mutations. A large number of human transcription factor genes were found to contain CAG repeats within their coding sequences. Analysis of the EMBL transcription factors database showed that many transcription factor genes of other eukaryotes, including genes involved in Drosophila embryo development, possess these repeats. Interestingly, CAG repeats are absent from prokaryotic transcription factors. Different sequence entries for the human TATA box binding protein showed a polymorphism in the length of the CAG repeat in this gene, suggesting that loci other than those already known to be associated with genetic diseases may be possible sites for repeat instability related disorders. On the basis of our findings in this database analysis, we propose a role for CAG repeats as cis-acting regulatory elements involved in fine-tuning gene expression.
ABSTRACT
Objective To study the gene mutation and clinical characteristics of hereditary spinocerebellar ataxia type 7 (SCA7).Methods The regions of SCA7 gene containing CAG repeat were amplified by means of polymerase chain reaction (PCR) and polyacrylamide gelelectrophoresis (PAGE) technique in 112 patients with autosomal dominant SCA from 92 families, 16 sporadic SCA patients, 71 family members and 60 healthy controls. The abnormal allele fragments were sequenced by ABI377 DNA sequencing machine. The correlation between clinical manifestations and CAG repeat size in SCA7 gene product was analyzed. Results 2 patients of 6 members in 1 SCA7 family carried a 71-repeat allele. The main clinic features included ataxia, hypopsia, axanthocyanopsia and retinal pigmental degeneration. Alleles from 7 to 9 repeats were seen in the other 4 healthy members. CAG repeats from 6 to 21 were found in other 126 SCA patients, 71 family members and 60 healthy controls. Conclusions Expanded triplet repeats in SCA7 gene contributes to the pathologic phenotype, and molecular genetic analysis is effective for the diagnosis of SCA7. Retinal pigmental degeneration is an important characteristic of SCA7.