cDNAs with long CAG trinucleotide repeats from human brain

Abstract

Twelve diseases, most with neuropsychiatric features, arise from trinucleotide repeat expansion mutations. Expansion mutations may also cause a number of other disorders, including several additional forms of spinocerebellar ataxia, bipolar affective disorder, schizophrenia, and autism. To obtain candiate genes for these disorders, cDNA libraries from adult and fetal human brain were screened at high stringency for clones containing CAG repeats. Nineteen cDNAs were isolated and mapped to chromosomes 1, 2, 4, 6, 7, 8, 9, 12, 16, 19, 20, and X. The clones contain between 4 and 17 consecutive CAG, CTG, TCG, or GCA triplets. Clone H44 encodes 40 consecutive glutamines, more than any other entry in the nonredundant GenBank protein database and well within the range that causes neuronal degeneration in several of the glutamine expansion diseases. Eight cDNAs encode 15 or more consecutive glutamine residues, suggesting that the gene products may function as transcription factors, with a potential role in the regulation of neurodevelopment or neuroplasticity. In particular, the conceptual translation of clone CTG3a contains 18 consecutive glutamines and is 45% identical to the C-terminal 306 residues of the mouse numb gene product. These genes are therefore candidates for diseases featuring anticipation, neurodegeneration, or abnormalities of neurodevelopment.

Association of CAG repeat loci on chromosome 22 with schizophrenia and bipolar disorder

“…The mRNA for this repeat-containing region was also identified in a study designed to pick up CAG repeatcontaining genes expressing in the brain. 31 The loci, 22CH2 and 22CH3 containing nine and eight repeats, respectively, were chosen over 22CH5 (eight CAG repeats) and 22CH6 (nine CAG repeats) because both of the former were in the vicinity of previously implicated markers. Furthermore, both 22CH2 and 22CH3 were found in the coding regions and were expressed in the brain, with the repeats coding for glutamine.…”

Identification of candidate genes on chromosome band 20q12 by physical mapping of translocation breakpoints found in myeloid leukemia cell lines

“…These include known and previously mapped genes (MYBL2, TNRC9/CAGF9, h-l(3)mbt) (Noben-Trauth et al, 1996;Margolis et al, 1997;Koga et al, 1999), a mapped UniGene (CGI-53) (Lai et al, 2000), an unknown mapped EST (sts-T63166), and an exontrapped transcript not previously mapped (SGK). The h-l(3)mbt gene encodes a member of the polycomb group family of proteins and is the human homologue of a tumor suppressor gene in Drosophila (Koga et al, 1999).…”

Detection of polyglutamine expansion in a new acidic protein: a candidate for childhood onset schizophrenia?

“…Polymorphic and/or long CAG repeats (n = 20) consisting of more than 10 consecutive units and previously found in human cDNA libraries [15][16][17] were also tested including 2.116, 2.119, i.181, i.182, 15 12501r, b01500t, and g02502r, 16 and CTG1a, CTG3a, CTG4a, CTG7a, CTG20a, CAGF9, F28, H1, H16, H26, H32, H38, H39, H44, H45, L69, L85, L114, L234, and L237, some of them predicted to code for a polygln stretch. 17 Finally, seven CAG/CTG repeats (GCT1C9, GCT4B10, GCT5E11, GCT16E06, GCT10D04, GCT10C10, and GCT10H06) isolated from genomic DNA and consisting of more than 15 consecutive units were tested as well. 18 The selection and use of primers suitable for detection of CAG expansion in DNAs from COS family NFI was performed as previously described.…”

“…Twenty-seven CAG repeats found in cDNAs [15][16][17] and CAG/CTG repeats isolated from genomic DNA 18 consisting of more than 10-15 consecutive units were also tested for expansion in NFI (see Methods). All the candidates tested showed unenlarged CAG repeat alleles, and no difference in the size Figure 1 Detection of PGE in COS. Electrophoresis was performed on 50 g (4-20% polyacrylamide gradient gels) or 60 g (long 10% polyacrylamide gels) of protein from LCL extracts (see Table 1).…”