Faculty Opinions recommendation of Most meiotic CAG repeat tract-length alterations in yeast are SPO11 dependent.

To examine the chromosomal stability of repetitions of the trinucleotide CAG, we have cloned CAG repeat tracts onto the 3' end of the Saccharomyces cerevisiae ADE2 gene and placed the appended gene into the ARO2 locus of chromosome VII. Examination of chromosomal DNA from sibling colonies arising from clonal expansion of strains harboring repeat tracts showed that repeat tracts often change in length. Most changes in tract length are decreases, but rare increases also occur. Longer tracts are more unstable than smaller tracts. The most unstable tracts, of 80 to 90 repeats, undergo changes at rates as high as 3 x 10(-2) changes per cell per generation. To examine whether repeat orientation or adjacent sequences alter repeat stability, we constructed strains with repeat tracts in both orientations, either with or without sequences 5' to ADE2 harboring an autonomously replicating sequence (ARS; replication origin). When CAG is in the ADE2 coding strand of strains harboring the ARS, the repeat tract is relatively stable regardless of the orientation of ADE2. When CTG is in the ADE2 coding strand of strains harboring the ARS, the repeat tract is relatively unstable regardless of the orientation of ADE2. Removal of the ARS as well as other sequences adjacent to the 5' end of ADE2 alters the orientation dependence such that stability now depends on the orientation of ADE2 in the chromosome. These results suggest that the proximity of an ARS or another sequence has a profound effect on repeat stability.

Download Full-text

Androgen Receptor Gene CAG Trinucleotide Repeats in Anovulatory Infertility and Polycystic Ovaries

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.85.9.6832 ◽

2000 ◽

Vol 85 (9) ◽

pp. 3484-3488 ◽

Cited By ~ 58

Author(s):

Amparo Mifsud ◽

Sylvia Ramirez ◽

E. L. Yong

Keyword(s):

Androgen Receptor ◽

Trinucleotide Repeat ◽

Age Of Onset ◽

Receptor Gene ◽

Normal Serum ◽

Cag Repeat ◽

Polycystic Ovaries ◽

Repeat Tract ◽

Serum Androgens ◽

Anovulatory Infertility

Abstract Hyperandrogenism is currently thought to be central to the pathogenesis of polycystic ovarian syndrome (PCOS), a common endocrine disorder in premenopausal women characterized by irregular menstruation and anovulatory infertility. Although hyperandrogenism is characteristic, some women with PCOS have normal serum androgen levels. All androgens act through the X-linked androgen receptor (AR), the N-terminal domain of which contains a polyglutamine tract encoded by a highly polymorphic CAG trinucleotide repeat tract. Recently, variations in this CAG microsatellite tract, while remaining within the normal polymorphic range (11–38 CAGs), have been inversely correlated with receptor activity. Thus, short tracts are associated with high intrinsic AR activity and increased severity and earlier age of onset of the androgen-regulated tumor prostate cancer, whereas longer CAG tracts are associated with low AR activity and oligospermic infertility. To investigate the role of the CAG repeat tract in PCOS, we measured its length in 91 patients with ultrasound diagnosis of polycystic ovaries, irregular menstrual cycles, and anovulatory infertility and compared them to 112 control subjects of proven fertility with regular menses. Fluorescent-labeled DNA fragments containing the CAG repeat tract were amplified from leucocytic DNA, and their lengths were compared with internal size markers on an automated DNA Sequencer. There were no differences in the mean CAG length between patients and controls when both alleles were considered together or separately. Because there is a subset of PCOS patients whose serum androgens are normal, we compared differences in CAG length between patients whose serum testosterone (T) levels were below the normal laboratory mean, to those that were higher. There was a trend for a lower mean CAG biallelic length among anovulatory patients with T less than 1.73 nmol/L compared with those whose T was more than 1.73 nmol/L (22.47 ± 0.36 vs. 23.25 ± 0.29). This difference in CAG length between patients with low and high T levels (20.38 ± 0.51 vs. 21.98 ± 0.29) was highly significant (P = 0.004) when only the shorter allele of each individual was considered. Ethnic differences were also evident in our data; Indian subjects had a significantly shorter AR-CAG length compared with Chinese, being 22.08 ± 0.50 and 23.16 ± 0.17, respectively. Our data indicate an association between short CAG repeat length and the subset of anovulatory patients with low serum androgens, suggesting that the pathogenic mechanism of polycystic ovaries in these patients could be due to the increased intrinsic androgenic activity associated with short AR alleles.

Download Full-text

Mapping the Polarity of Changes That Occur in Interrupted CAG Repeat Tracts in Yeast

Molecular and Cellular Biology ◽

10.1128/mcb.18.8.4597 ◽

1998 ◽

Vol 18 (8) ◽

pp. 4597-4604 ◽

Cited By ~ 17

Author(s):

Debra J. Maurer ◽

Brennon L. O’Callaghan ◽

Dennis M. Livingston

Keyword(s):

Mismatch Repair ◽

Trinucleotide Repeat ◽

Cag Repeat ◽

Yeast Cells ◽

Wild Type ◽

Repeat Tract ◽

Repeat Units ◽

Length Changes ◽

Mutant Cells ◽

Lagging Strand

ABSTRACT To explore the mechanisms by which CAG trinucleotide repeat tracts undergo length changes in yeast cells, we examined the polarity of alterations with respect to an interrupting CAT trinucleotide near the center of the tract. In wild-type cells, in which most tract changes are large contractions, the changes that retain the interruption are biased toward the 3′ end of the repeat tract (in reference to the direction of lagging-strand synthesis). In rth1/rad27mutant cells that are defective in Okazaki fragment maturation, the tract expansions are biased to the 5′ end of the repeat tract, while the tract contractions that do not remove the interruption occur randomly on either side of the interruption. In msh2 mutant cells that are defective in the mismatch repair machinery, neither the small changes of one or two repeat units nor the larger contractions attributable to this mutation are biased to either side of the interruption. The results of this study are discussed in terms of the molecular paths leading to expansions and contractions of repeat tracts.

Download Full-text

Effect of Repeat Tract Length on Expansions and Deletions of CTG.CAG Repeats Mediated by Mismatch Repair in Escherichia coli

Biochemical Society Transactions ◽

10.1042/bst028a168 ◽

2000 ◽

Vol 28 (5) ◽

pp. A168-A168

Author(s):

P. Parniewski ◽

A. Jaworski ◽

R. D. Wells ◽

R. P. Bowater

Keyword(s):

Escherichia Coli ◽

Mismatch Repair ◽

Tract Length ◽

Repeat Tract

Download Full-text

A polyalanine antibody for the diagnosis of oculopharyngeal muscular dystrophy and polyalanine-related diseases

MNI Open Research ◽

10.12688/mniopenres.12765.1 ◽

2017 ◽

Vol 1 ◽

pp. 1

Author(s):

Shawn J. Stochmanski ◽

François Blondeau ◽

Martine Girard ◽

Pascale Hince ◽

Daniel Rochefort ◽

...

Keyword(s):

Muscular Dystrophy ◽

Trinucleotide Repeat ◽

Late Onset ◽

Cag Repeat ◽

Spinocerebellar Ataxia Type ◽

Causative Mutation ◽

Oculopharyngeal Muscular Dystrophy ◽

Spinocerebellar Ataxia Type 3 ◽

Repeat Tract ◽

Repeat Expansions

Eighteen severe human diseases have so far been associated with trinucleotide repeat expansions coding for either polyalanine (encoded by a GCN repeat tract) or polyglutamine (encoded by a CAG repeat tract). Among them, oculopharyngeal muscular dystrophy (OPMD), spinocerebellar ataxia type-3 (SCA3), and Huntington’s disease (HD) are late-onset autosomal-dominant disorders characterized by the presence of intranuclear inclusions (INIs). We have previously identified the OPMD causative mutation as a small expansion (from 2 in normal to 7 in disease) of a GCG repeat tract in the PABPN1 gene. In addition, -1 ribosomal frameshifting has been reported to occur in expanded CAG repeat tracts in the ATXN3 (SCA3) and HTT (HD) genes, resulting in the translation of a hybrid CAG/GCA repeat tract and the production of a polyalanine-containing peptide. Previous studies on OPMD suggest that polyalanine-induced toxicity is very sensitive to the dosage and length of the alanine stretch. Here we report the characterization of a polyclonal antibody that selectively recognizes pathological expansions of polyalanine in PABPN1. Furthermore, our antibody also detects the presence of alanine proteins in INIs of SCA3 and HD patient samples.

Download Full-text

What is the Pathogenic CAG Expansion Length in Huntington’s Disease?

Journal of Huntington s Disease ◽

10.3233/jhd-200445 ◽

2021 ◽

Vol 10 (1) ◽

pp. 175-202

Author(s):

Jasmine Donaldson ◽

Sophie Powell ◽

Nadia Rickards ◽

Peter Holmans ◽

Lesley Jones

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Confidence Intervals ◽

Age At Onset ◽

Cag Repeat ◽

Genetic Modifiers ◽

Tract Length ◽

Cag Expansion ◽

Age Dependent ◽

Step Mechanism

Huntington’s disease (HD) (OMIM 143100) is caused by an expanded CAG repeat tract in the HTT gene. The inherited CAG length is known to expand further in somatic and germline cells in HD subjects. Age at onset of the disease is inversely correlated with the inherited CAG length, but is further modulated by a series of genetic modifiers which are most likely to act on the CAG repeat in HTT that permit it to further expand. Longer repeats are more prone to expansions, and this expansion is age dependent and tissue-specific. Given that the inherited tract expands through life and most subjects develop disease in mid-life, this implies that in cells that degenerate, the CAG length is likely to be longer than the inherited length. These findings suggest two thresholds— the inherited CAG length which permits further expansion, and the intracellular pathogenic threshold, above which cells become dysfunctional and die. This two-step mechanism has been previously proposed and modelled mathematically to give an intracellular pathogenic threshold at a tract length of 115 CAG (95% confidence intervals 70– 165 CAG). Empirically, the intracellular pathogenic threshold is difficult to determine. Clues from studies of people and models of HD, and from other diseases caused by expanded repeat tracts, place this threshold between 60– 100 CAG, most likely towards the upper part of that range. We assess this evidence and discuss how the intracellular pathogenic threshold in manifest disease might be better determined. Knowing the cellular pathogenic threshold would be informative for both understanding the mechanism in HD and deploying treatments.

Download Full-text

Vocal Tract Length Estimation Using Accumulated Means of Formants and Its Effects on Speaker-Normalization

IEEE/ACM Transactions on Audio Speech and Language Processing ◽

10.1109/taslp.2021.3060172 ◽

2021 ◽

Vol 29 ◽

pp. 1049-1064

Author(s):

Tadashi Sakata ◽

Naomitsu Ikeda ◽

Yuichi Ueda ◽

Akira Watanabe

Keyword(s):

Vocal Tract ◽

Speaker Normalization ◽

Tract Length ◽

Length Estimation

Download Full-text

Differential Diagnosis of Chorea—HIV Infection Delays Diagnosis of Huntington’s Disease by Years

Brain Sciences ◽

10.3390/brainsci11060710 ◽

2021 ◽

Vol 11 (6) ◽

pp. 710

Author(s):

Jannis Achenbach ◽

Simon Faissner ◽

Carsten Saft

Keyword(s):

Hiv Infection ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Disease Onset ◽

Diagnostic Delay ◽

Depression Scale ◽

Cag Repeat ◽

Psychiatric Disease ◽

Disease Manifestation ◽

Cross Sectional

Background: There is a broad range of potential differential diagnoses for chorea. Besides rare, inherited neurodegenerative diseases such as Huntington’s disease (HD) chorea can accompany basal ganglia disorders due to vasculitis or infections, e.g., with the human immunodeficiency virus (HIV). The clinical picture is complicated by the rare occurrence of HIV infection and HD. Methods: First, we present a case suffering simultaneously from HIV and HD (HIV/HD) focusing on clinical manifestation and disease onset. We investigated cross-sectional data regarding molecular genetic, motoric, cognitive, functional, and psychiatric disease manifestation of HIV/HD in comparison to motor-manifest HD patients without HIV infection (nonHIV/HD) in the largest cohort of HD patients worldwide using the registry study ENROLL-HD. Data were analyzed using ANCOVA analyses controlling for covariates of age and CAG repeat length between groups in IBM SPSS Statistics V.25. Results: The HD diagnosis in our case report was delayed by approximately nine years due to the false assumption that the HIV infection might have been the cause of chorea. Out of n = 21,116 participants in ENROLL-HD, we identified n = 10,125 motor-manifest HD patients. n = 23 male participants were classified as suffering from HIV infection as a comorbidity, compared to n = 4898 male non-HIV/HD patients. Except for age, with HIV/HD being significantly younger (p < 0.050), we observed no group differences regarding sociodemographic, genetic, educational, motoric, functional, and cognitive parameters. Male HIV/HD patients reported about a 5.3-year-earlier onset of HD symptoms noticed by themselves compared to non-HIV/HD (p < 0.050). Moreover, patients in the HIV/HD group had a longer diagnostic delay of 1.8 years between onset of symptoms and HD diagnosis and a longer time regarding assessment of first symptoms by the rater and judgement of the patient (all p < 0.050). Unexpectedly, HIV/HD patients showed less irritability in the Hospital Anxiety and Depression Scale (all p < 0.05). Conclusions: The HD diagnosis in HIV-infected male patients is secured with a diagnostic delay between first symptoms noticed by the patient and final diagnosis. Treating physicians therefore should be sensitized to think of potential alternative diagnoses in HIV-infected patients also afflicted by movement disorders, especially if there is evidence of subcortical atrophy and a history of hyperkinesia, even without a clear HD-family history. Those patients should be transferred for early genetic testing to avoid further unnecessary diagnostics and improve sociomedical care.

Download Full-text