scholarly journals Molecular characteristics of Machado-Joseph disease mutation in 25 newly described Brazilian families

1997 ◽  
Vol 20 (4) ◽  
pp. 717-724 ◽  
Author(s):  
Iscia Lopes-Cendes ◽  
Hélio G.A. Teive ◽  
Francisco Cardoso ◽  
Erika M. Viana ◽  
Maria E. Calcagnotto ◽  
...  
Keyword(s):  
Late Onset ◽  
Age At Onset ◽  
Collaborative Study ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Causative Mutation ◽  
Molecular Characteristics ◽  
Spinocerebellar Ataxias ◽  
Extrapyramidal Signs ◽  
Machado Joseph Disease

Machado-Joseph disease (MJD) is a form of autosomal dominant spinocerebellar ataxia first described in North-American patients originating from the Portuguese islands of the Azores. Clinically this disorder is characterized by late onset progressive ataxia with associated features, such as: ophthalmoplegia, pyramidal and extrapyramidal signs and distal muscular atrophies. The causative mutation is an expansion of a CAG repeat in the coding region of the MJD1 gene. We have identified 25 unrelated families segregating the MJD mutation during a large collaborative study of spinocerebellar ataxias in Brazil. In the present study a total of 62 family members were genotyped for the CAG repeat in the MJD1 gene, as well as 63 non-MJD individuals (126 normal chromosomes), used as normal controls. We observed a wide gap between the size range of the normal and expanded CAG repeats: the normal allele had from 12 to 33 CAGs (mean = 23 CAGs), whereas the expanded alleles ranged from 66 to 78 CAGs (mean = 71.5 CAGs). There were no differences in CAG tract length according to gender of affected individuals or transmitting parent. We observed a significant negative correlation between age at onset of the disease and length of the CAG tract in the expended allele (r = -0.6, P = 0.00006); however, the size of the expanded CAG repeat could explain only about 40% of the variability in age at onset (r2 = 0.4). There was instability of the expanded CAG tract during transmission from parent to offspring, both expansions and contractions were observed; however, there was an overall tendency for expansion, with a mean increase of +2.4 CAGs. The tendency for expansion appeared to the greater in paternal (mean increase of +3.5 CAGs) than in maternal transmissions (mean increase of +1.3 CAGs). Anticipation was observed in all transmissions in which ages at onset for parent and offspring were known; however, anticipation was not always associated with an increase in the expanded CAG repeat length. Our results indicate that the molecular diagnosis of MJD can be confirmed or excluded in all suspected individuals, since alleles of intermediary size were not observed.

scholarly journals Huntington disease update: new insights into the role of repeat instability in disease pathogenesis

2021 ◽  
Vol 33 (4) ◽  
pp. 293-300
Author(s):  
Larissa Arning ◽  
Huu Phuc Nguyen
Keyword(s):  
Disease Progression ◽  
Dna Sequences ◽  
Huntington Disease ◽  
Trinucleotide Repeat ◽  
Age At Onset ◽  
Repeat Sequence ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Causative Mutation ◽  
Cognitive Disability

Abstract The causative mutation for Huntington disease (HD), an expanded trinucleotide repeat sequence in the first exon of the huntingtin gene (HTT) is naturally polymorphic and inevitably associated with disease symptoms above 39 CAG repeats. Although symptomatic medical therapies for HD can improve the motor and non-motor symptoms for affected patients, these drugs do not stop the ongoing neurodegeneration and progression of the disease, which results in severe motor and cognitive disability and death. To date, there is still an urgent need for the development of effective disease‐modifying therapies to slow or even stop the progression of HD. The increasing ability to intervene directly at the roots of the disease, namely HTT transcription and translation of its mRNA, makes it necessary to understand the pathogenesis of HD as precisely as possible. In addition to the long-postulated toxicity of the polyglutamine-expanded mutant HTT protein, there is increasing evidence that the CAG repeat-containing RNA might also be directly involved in toxicity. Recent studies have identified cis- (DNA repair genes) and trans- (loss/duplication of CAA interruption) acting variants as major modifiers of age at onset (AO) and disease progression. More and more extensive data indicate that somatic instability functions as a driver for AO as well as disease progression and severity, not only in HD but also in other polyglutamine diseases. Thus, somatic expansions of repetitive DNA sequences may be essential to promote respective repeat lengths to reach a threshold leading to the overt neurodegenerative symptoms of trinucleotide diseases. These findings support somatic expansion as a potential therapeutic target in HD and related repeat expansion disorders.

scholarly journals Clinical and molecular characteristics of a Brazilian family with spinocerebellar ataxia type 1

1996 ◽  
Vol 54 (3) ◽  
pp. 412-418 ◽  
Author(s):  
Iscia Lopes-Cendes ◽  
Carlos E. Steiner ◽  
Isabel Silveira ◽  
Walter Pinto-Junior ◽  
Jayme A. Maciel ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Late Onset ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Molecular Characteristics ◽  
Spinocerebellar Ataxias ◽  
Dominant Type ◽  
Expanded Allele ◽  
Mean Size ◽  
Autosomal Dominant Type

The spinocerebellar ataxias (SCAs) are a clinically and genetically heterogeneous group of late onset neurodegenerative disorders. To date, seven different genes causing autosomal dominant SCA have been mapped: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, SCA7 and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA1, MJD/SCA3 and DRPLA. We studied one Brazilian family segregating an autosomal dominant type of SCA. A total of ten individuals were examined and tested for the presence of the SCA1, MJD and DRPLA mutations. Three individuals, one male and two females, were considered affected based on neurological examination; ages at onset were: 32, 36 and 41 years. The first complaint in all three patients was gait ataxia which progressed slowly over the years. Six individuals showed one allele containing an expanded CAG repeat in the SCA1 gene. The mean size of the expanded allele was 48.2 CAG units. Instability of the expanded CAG tract was seen in the two transmissions that were observed in this family. In both occasions there was a contraction of the CAG tract. Our study demonstrates that SCA1 occurs in the Brazilian population. In addition, our results stress the importance of molecular studies in the confirmation of diagnosis and for pre-symptomatic testing in SCAs.

scholarly journals The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

2021 ◽  
Vol 10 (1) ◽  
pp. 7-33
Author(s):  
Darren G. Monckton
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Human Genetics ◽  
Age At Onset ◽  
Cag Repeat ◽  
Model Systems ◽  
Causative Mutation ◽  
Inverse Association ◽  
Independent Manner ◽  
Dna Mismatch

The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders.

scholarly journals Modulation at Age of Onset in Tunisian Huntington Disease Patients: Implication of New Modifier Genes

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Dorra Hmida-Ben Brahim ◽  
Marwa Chourabi ◽  
Sana Ben Amor ◽  
Imed Harrabi ◽  
Saoussen Trabelsi ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Age At Onset ◽  
Specific Effect ◽  
Modifier Genes ◽  
Cag Repeats ◽  
Causative Mutation ◽  
Cag Expansion ◽  
Tunisian Patients

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. The causative mutation is an expansion of more than 36 CAG repeats in the first exon of IT15 gene. Many studies have shown that the IT15 interacts with several modifier genes to regulate the age at onset (AO) of HD. Our study aims to investigate the implication of CAG expansion and 9 modifiers in the age at onset variance of 15 HD Tunisian patients and to establish the correlation between these modifiers genes and the AO of this disease. Despite the small number of studied patients, this report consists of the first North African study in Huntington disease patients. Our results approve a specific effect of modifiers genes in each population.

Spinocerebellar ataxia type 6

Neurology ◽  
1997 ◽  
Vol 49 (5) ◽  
pp. 1238-1243 ◽  
Author(s):  
R. Matsumura ◽  
N. Futamura ◽  
Y. Fujimoto ◽  
S. Yanagimoto ◽  
H. Horikawa ◽  
...  
Keyword(s):  
Family History ◽  
Cerebellar Ataxia ◽  
Age At Onset ◽  
Repeat Expansion ◽  
Repeat Length ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Spinocerebellar Ataxia Type ◽  
Cag Repeat Expansion ◽  
Spinocerebellar Ataxia Type 6

Spinocerebellar ataxia type 6 (SCA6) is a newly classified autosomal-dominant cerebellar ataxia (ADCA) associated with CAG repeat expansion. We screened 111 patients with cerebellar ataxia for the SCA6 mutation. Of these, 35 patients were found to have expanded CAG repeats in the SCA6 gene, indicating that second to SCA3, SCA6 is the most common ADCA in Japan. Expanded alleles ranged from 21 to 29 repeats, whereas normal alleles had seven to 17 repeats. There was no change in the CAG repeat length during meiosis. The age at onset was inversely correlated with the repeat length. The main clinical feature of the 35 patients with SCA6 was slowly progressive cerebellar ataxia; multisystem involvement was not common. The 35 patients included nine cases without apparent family history of cerebellar ataxia. The sporadic cases had smaller CAG repeats (21 or 22 repeats) and a later age at onset (64.9 ± 4.9 years) than the other cases with established family history. We also identified one patient who was homozygous for the SCA6 repeat expansion. The homozygote showed an earlier age of onset and more severe clinical manifestations than her sister, a heterozygote carrying an expanded allele with the same repeat length as the homozygote. This finding suggests that the dosage of the CAG repeat expansion plays an important role in phenotypic expression in SCA6.

scholarly journals NATURAL SELECTION AT THE MJD LOCUS: PHENOTYPIC DIVERSITY, SURVIVAL AND FERTILITY AMONG MACHADO-JOSEPH DISEASE PATIENTS FROM THE AZORES

2001 ◽  
Vol 33 (3) ◽  
pp. 361-373 ◽  
Author(s):  
M. LIMA ◽  
M. SMITH ◽  
C. SILVA ◽  
A. ABADE ◽  
F. MAYER ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Phenotypic Diversity ◽  
Age At Onset ◽  
Cag Repeats ◽  
Early Age ◽  
Coding Region ◽  
Differential Survival ◽  
Clinical Type ◽  
Machado Joseph Disease

Machado-Joseph Disease (MJD) is an autosomal dominant neurodegenerative disorder of adult onset, associated with the expansion of a (CAG)n tract in the coding region of the causative gene, localized on 14q32.1. Machado-Joseph Disease shows non-Mendelian features typical of other triplet repeat disorders, including clinical heterogeneity, variable age at onset and anticipation. Three phenotypes have been proposed (clinical types 1, 2 and 3). Type 1 is associated with early age at onset and a high repeat number of the CAG sequence, and Types 2 and 3 have later onset and lower numbers of CAG repeats. This paper investigates whether there is selection against the MJD gene, acting through differential survival, nuptiality and fertility associated with clinical type and age at onset. The study sample comprised 40 MJD patients from the Azores (Portugal) having fully documented reproductive histories and known dates of death. The proportion of married patients of each clinical type increased from 0·22 among Type 1 patients, to 0·40 in Type 2 and 0·95 in Type 3. Age at onset and length of survival were also associated with marital status, with the married cases having later mean age at onset and longer mean survival time. In the whole sample, clinical type was associated with fertility, with significantly fewer children born to Type 1 patients. Among married patients clinical type was not associated with age at marriage, reproductive span or number of children. No reduction of fertility was detected among married patients in whom the onset of MJD was below the age of 50. The authors’ interpretation of these results is that the high-repeat CAG haplotypes associated with early age at onset and clinical Type 1 are selected against through reduced survival and fertility. The fertility component of selection is mediated by nuptiality rather than marital fertility.

scholarly journals Association between estrogen and androgen receptor genes and prostate cancer risk

2009 ◽  
Vol 160 (1) ◽  
pp. 101-106 ◽  
Author(s):  
Nathalie Nicolaiew ◽  
Geraldine Cancel-Tassin ◽  
Abdel Rahmene Azzouzi ◽  
Beatrice Le Grand ◽  
Philippe Mangin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Late Onset ◽  
Age At Onset ◽  
Prostate Cancer Risk ◽  
Cag Repeat ◽  
Tumor Aggressiveness ◽  
Normal Prostate ◽  
First Intron ◽  
Design And Methods ◽  
Prostate Growth

ObjectiveProstate cancer (PC) is one of the principal causes of death among men. Steroid hormones are involved in normal prostate growth and carcinogenesis. The purpose of our study was to investigate the effects on PC risk of polymorphisms from three steroid hormone receptor genes: the androgen (AR), and the α (ESR1) and β (ESR2) estrogen receptors.Design and methodsThe study was performed on a Caucasian population of 1045 PC patients and 814 controls. Using a logistic regression model, the different alleles and genotypes from those polymorphisms were analyzed according to case/control status, the tumor aggressiveness, and the age at onset.ResultsA significant association between PC risk and the pooled 4/5, 5/6, and 6/6 genotypes of the GGGA repeat located in the first intron of ESR1 (odds ratio (OR)=3.00, 95% CI=1.32–6.82, P=0.008) was observed. When we stratified the cases, this association was confined to patients with a Gleason score of 2–4 (OR=8.34, 95% CI=2.91–23.91, P<0.0001) or late onset PC (OR=2.91, 95% CI=1.22–6.93, P=0.016). An association between a short AR CAG repeat (less than 17 repeats) was also observed among patients with late onset PC (OR=2.34, 95% CI=1.15–4.76, P=0.019).ConclusionsThese findings suggest that the GGGA repeat from ESR1 and the CAG repeat from AR may be associated with risk of late onset PC.

scholarly journals Late-onset Huntington’s disease with 40–42 CAG expansion

2019 ◽  
Vol 41 (4) ◽  
pp. 869-876 ◽  
Author(s):  
Elisa Capiluppi ◽  
Luca Romano ◽  
Paola Rebora ◽  
Lorenzo Nanetti ◽  
Anna Castaldo ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Late Onset ◽  
Age At Onset ◽  
Clinical Manifestations ◽  
Cag Repeats ◽  
Cag Expansion

Abstract Introduction Huntington’s disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a CAG expansion greater than 35 in the IT-15 gene. There is an inverse correlation between the number of pathological CAG and the age of onset. However, CAG repeats between 40 and 42 showed a wider onset variation. We aimed to investigate potential clinical differences between patients with age at onset ≥ 60 years (late onset-HD) and patients with age at onset between 30 and 59 years (common-onset HD) in a cohort of patients with the same CAG expansions (40–42). Methods A retrospective analysis of 66 HD patients with 40–41–42 CAG expansion was performed. Patients were investigated with the Unified Huntington’s Disease Rating Scale (subitems I–II–III and Total Functional Capacity, Functional Assessment and Stage of Disease). Data were analysed using χ2, Fisher’s test, t test and Pearson’s correlation coefficient. GENMOD analysis and Kaplan-Meier analysis were used to study the disease progression. Results The age of onset ranged from 39 to 59 years in the CO subgroup, whereas the LO subgroup showed an age of onset from 60 to 73 years. No family history was reported in 31% of the late-onset in comparison with 20% in common-onset HD (p = 0.04). No difference emerged in symptoms of onset, in clinical manifestations and in progression of disease between the two groups. Conclusion There were no clinical differences between CO and LO subgroups with 40–42 CAG expansion. There is a need of further studies on environmental as well genetic variables modifying the age at onset.

scholarly journals Genetic testing for Spinocerebellar Ataxias (SCA) in Parkinsonism

2013 ◽  
Vol 28 (1) ◽  
pp. 16-23
Author(s):  
Md Siddiqur Rahman ◽  
Yoshitaka Nagai ◽  
H Akiko Popiel ◽  
Muzahed Uddin Ahmed ◽  
Md Jalal Uddin ◽  
...  
Keyword(s):  
Healthy Individual ◽  
Demographic Data ◽  
Venous Blood ◽  
Pcr Amplification ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Clinical Genetics ◽  
Spinocerebellar Ataxias ◽  
Product Size ◽  
Pcr Product

Objective: The study was conducted to find out Spinocerebellar Ataxias (SCA) by genetic analysis from those presenting with parkinsonism in the Neurology department of Mymensingh Medical College.Materials and methods: A sample of about 5ml blood was collected by venipuncture in EDTA tube with informed consent from the patients following institutional ethics committee approval by genetic study from 7 healthy people and 9 patients. The neurological disorder along with a complete physical and/or psychological, as well as family history and demographic data was recorded with a prescribed questionnaire by the neurologists of Mymensingh Medical College. Extraction of genomic DNA from the venous blood using FlexiGene DNA kit (Qiagen, Japan) was performed in Department of Medicine, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh. The extracted DNA was stored and accumulated and then these DNA were sent to Division of Clinical Genetics, Department of Medical Genetics, Osaka University Medical School, Suita, Osaka 565 0871, Japan for PCR and further analysis. PCR amplification of the CAG repeat was performed for the SCA1, SCA2, SCA3, SCA6 loci using primers SCA1N-F1 and SCA1N-R1, SCA2-F1 and SCA2-R1, MJDF1 and MJDR1, SCA6-F1 and SCA6-R1, respectively.Results: SCA1 PCR of both healthy individual and suspected PD patients DNA is about 250 bp (no. of CAG repeats=36). SCA2 PCR products reveal the DNA products of about 150 bp (no. of CAG repeats=23) except one patient that we suspected and it was sequenced and revealed 175bp (no. of CAG repeats=30). SCA3 PCR product size of both healthy individual and patient DNA is within about 250 (no. of CAG=11) to 300 bp (no. of CAG repeats=28) except one patient which is about 320bp and its CAG repeats is about 34. SCA6 PCR product size of both healthy individual and patient DNA is about 150bp (no. of CAG=16).Conclusion: This is the first time from Bangladesh regarding the range of CAG repeats in patients as well as healthy individual.

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