CAG/CTG and CGG/GCC Repeats in Human Brain Reference cDNAs: Outcome in Searching for New Dynamic Mutations

Albanèse, Véronique; Holbert, Sébastien; Saada, Claudine; Meier‐Ewert, Sebastian; Lèbre, Anne-Sophie; Moriniere, Stephanie; Bougueleret, Lydie; Gall, Isabelle Le; Weissenbach, Jean; Lennon, Greg; Lehrach, Hans; Cohen, Daniel; Cann, Howard M.; Néri, Christian

doi:10.1006/geno.1997.5130

Cited by 8 publications

(6 citation statements)

References 29 publications

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“…2), indicating that the coding region of clone A is complete. The 5Ј-UTR is exceptionally G/C-rich (84%) and contains a perfect run of six CAG repeats, although this number is considered to be just below the threshold length that would make it a candidate for polymorphic expansion (21). The 5Ј-end of the nucleotide sequence of clone A terminates in a NotI site.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Molecular and Catalytic Diversity among Human Diphosphoinositol-Polyphosphate Phosphohydrolases

Caffrey

Safrany

Yang

et al. 2000

Journal of Biological Chemistry

109

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The turnover of the "high energy" diphosphoinositol polyphosphates by Ca 2؉ -and cyclic nucleotide-modulated enzymes is considered a regulatory, molecular switching activity. Target processes may include intracellular trafficking. Following our earlier identification of a prototype human diphosphoinositol-polyphosphate phosphohydrolase (hDIPP1), we now describe new 21-kDa human isoforms, hDIPP2␣ and hDIPP2␤, distinguished from each other solely by hDIPP2␤ possessing one additional amino acid (Gln 86 ). Candidate DIPP2␣ and DIPP2␤ homologues in rat and mouse were also identified. The rank order for catalytic activity is hDIPP1 > hDIPP2␣ > hDIPP2␤. Differential expression of hDIPP isoforms may provide flexibility in response times of the molecular switches. The 76% identity between hDIPP1 and the hDIPP2s includes conservation of an emerging signature sequence, namely, a Nudt (MutT) motif with a GX 2 GX 6 G carboxy extension. Northern and Western analyses indicate expression of hDIPP2s is broad but atypically controlled; these proteins are translated from multiple mRNAs that differ in the length of the 3-untranslated region because of utilization of an array of alternative (canonical and noncanonical) polyadenylation signals. Thus, cells can recruit sophisticated molecular processes to regulate diphosphoinositol polyphosphate turnover.The considerable energy burden that is required to sustain rapid, ongoing cellular turnover of the "high energy" diphosphoinositol polyphosphates (PP-

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Section: Methodsmentioning

confidence: 99%

Discovery of Molecular and Catalytic Diversity among Human Diphosphoinositol-Polyphosphate Phosphohydrolases

Caffrey

Safrany

Yang

et al. 2000

Journal of Biological Chemistry

109

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“…Initially, searches were carried out for the presence of unstable CAG tracts in complementary DNA libraries [44], and repeat expansion detection (RED) has been used to screen for CAG tracts within a schizophrenic population [45•]. Unstable triplet repeat tracts not yet associated with a disease, such as ERDA1 [46,47] and SEF2-1B [48], were identified as possible candidate loci that may contribute to the anticipation reported in psychotic cohorts.…”

Section: Cag•ctg Tracts Not Currently Associated With Diseasementioning

confidence: 99%

Anticipation and CAG•CTG repeat expansion in schizophrenia and bipolar affective disorder

Fortune

Kennedy²,

Vincent

2003

Curr Psychiatry Rep

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The genetic contribution to the etiologies of schizophrenia and bipolar affective disorder (BPAD) has been considered for many decades, with twin, family, and adoption studies indicating consistently that the familial clustering of affected individuals is accounted for mainly by genetic factors. Despite the strong evidence for a genetic component, very little is understood about the underlying genetic and molecular mechanisms for schizophrenia and BPAD. In the early 1990s, after the discovery of "dynamic mutation" or "unstable DNA" as a molecular basis for the genetic anticipation observed in Huntington's disease, myotonic dystrophy, and many others, and the recently rediscovered, albeit still controversial, evidence for genetic anticipation in major psychoses, the genetic epidemiology of schizophrenia and BPAD was re-evaluated to demonstrate strong endorsement for the unstable DNA model. Many of the non-Mendelian genetic features of schizophrenia and BPAD could be explained by the behaviour of unstable DNA, and several molecular genetic approaches became available for testing the unstable DNA hypothesis. However, despite promising findings in the mid-1990s, no trinucleotide repeat expansion has yet been identified as a cause of idiopathic schizophrenia or BPAD.

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“…DNA libraries and databases, i.e., cDNA library screening [Li et al, 1993;Margolis et al, 1997;Bulle et al, 1997;Albanese et al, 1998], genomic library screening [Gastier et al, 1996;Philibert et al, 1998;Kleiderlein et al, 1998;Mangel et al, 1998], cDNA sequences in databases [Neri et al, 1996]; also more focussed strategies involving screening patient-specific genomic libraries, such as Direct Identification of Repeat Expansion and Cloning Technique (DIRECT) [Sanpei et al, 1996], Rapid Analysis, Pooled Isolation and Detection (RAPID) [Koob et al, 1998], di-or trinucleotide polymerase reaction and capture (DTC) [Inoue et al, 1999] and including a variation of DIRECT and RAPID [Vincent et al, in press]. 2.…”

Section: Molecular Studies Of Trinucleotide Repeats In Major Psychosimentioning

confidence: 99%

The unstable trinucleotide repeat story of major psychosis

et al. 2000

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New hopes for cloning susceptibility genes for schizophrenia and bipolar affective disorder followed the discovery of a novel type of DNA mutation, namely unstable DNA. One class of unstable DNA, trinucleotide repeat expansion, is the causal mutation in myotonic dystrophy, fragile X mental retardation, Huntington disease and a number of other rare Mendelian neurological disorders. This finding has led researchers in psychiatric genetics to search for unstable DNA sites as susceptibility factors for schizophrenia and bipolar affective disorder. Increased severity and decreased age at onset of disease in successive generations, known as genetic anticipation, was reported for undifferentiated psychiatric diseases and for myotonic dystrophy early in the twentieth century, but was initially dismissed as the consequence of ascertainment bias. Because unstable DNA was demonstrated to be a molecular substrate for genetic anticipation in the majority of trinucleotide repeat diseases including myotonic dystrophy, many recent studies looking for genetic anticipation have been performed for schizophrenia and bipolar affective disorder with surprisingly consistent positive results. These studies are reviewed, with particular emphasis placed on relevant sampling and statistical considerations, and concerns are raised regarding the interpretation of such studies. In parallel, molecular genetic investigations looking for evidence of trinucleotide repeat expansion in both schizophrenia and bipolar disorder are reviewed. Initial studies of genome-wide trinucleotide repeats using the repeat expansion detection technique suggested possible association of large CAG/CTG repeat tracts with schizophrenia and bipolar affective disorder. More recently, three loci have been identified that contain large, unstable CAG/CTG repeats that occur frequently in the population and seem to account for the majority of large products identified using the repeat expansion detection method. These repeats localize to an intron in transcription factor gene SEF2-1B at 18q21, a site named ERDA1 on 17q21 with no associated coding region, and the 3' end of a gene on 13q21, SCA8, that is believed to be responsible for a form of spinocerebellar ataxia. At present no strong evidence exists that large repeat alleles at either SEF2-1B or ERDA1 are involved in the etiology of schizophrenia or bipolar disorder. Preliminary evidence suggests that large repeat alleles at SCA8 that are non-penetrant for ataxia may be a susceptibility factor for major psychosis. A fourth, but much more infrequently unstable CAG/CTG repeat has been identified within the 5' untranslated region of the gene, MAB21L1, on 13q13. A fifth CAG/CTG repeat locus has been identified within the coding region of an ion transporter, KCNN3 (hSKCa3), on 1q21. Although neither large alleles nor instability have been observed at KCNN3, this repeat locus has been extensively analyzed in association and family studies of major psychosis, with conflicting findings. Studies of polyglutamine containing genes i...

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CAG/CTG and CGG/GCC Repeats in Human Brain Reference cDNAs: Outcome in Searching for New Dynamic Mutations

Cited by 8 publications

References 29 publications

Discovery of Molecular and Catalytic Diversity among Human Diphosphoinositol-Polyphosphate Phosphohydrolases

Discovery of Molecular and Catalytic Diversity among Human Diphosphoinositol-Polyphosphate Phosphohydrolases

Anticipation and CAG•CTG repeat expansion in schizophrenia and bipolar affective disorder

The unstable trinucleotide repeat story of major psychosis

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