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

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.

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CRISPR/Cas9-based silencing of the ATXN1 gene in Spinocerebellar ataxia type 1 (SCA1) fibroblasts

10.1101/2020.07.04.187559 ◽

2020 ◽

Author(s):

Francesca Salvatori ◽

Mariangela Pappadà ◽

Mariaconcetta Sicurella ◽

Mattia Buratto ◽

Valentina Simioni ◽

...

Keyword(s):

Spinocerebellar Ataxia ◽

Neurodegenerative Disorder ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Rna Seq ◽

Coding Region ◽

Spinocerebellar Ataxia Type 1 ◽

Polyq Tract

AbstractSpinocerebellar Ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by a gain-of-function protein with toxic activities, containing an expanded polyQ tract in the coding region. Actually, there are no treatments available to delay the onset, stop or slow down the progression of this pathology. Many approaches developed over the years involve the use of siRNAs and antisense oligonucleotides (ASOs). Here we develop and validate a CRISPR/Cas9 therapeutic strategy in fibroblasts isolated from SCA1 patients. We started from the screening of 10 different sgRNAs able to recognize regions upstream and downstream the CAG repeats, in exon 8 of ATXN1 gene. The two most promising sgRNAs, G3 and G8, whose efficiency was evaluated with an in vitro system, significantly downregulated the ATXN 1 protein expression. This downregulation was due to the introduction of indels mutations into the ATXN1 gene. Notably, with an RNA-seq analysis, we demonstrated minimal off-target effects of our sgRNAs. These preliminary results support CRISPR/Cas9 as a promising approach for treated polyQ-expanded diseases.

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Sequence variation and size ranges of CAG repeats in the Machado-Joseph disease, spinocerebellar ataxia type 1 and androgen receptor genes

Human Molecular Genetics ◽

10.1093/hmg/4.9.1585 ◽

1995 ◽

Vol 4 (9) ◽

pp. 1585-1590 ◽

Cited By ~ 42

Author(s):

David C. Rubinsztein ◽

Jayne Leggo ◽

Gerhard A. Coetzee ◽

Ryan A. Irvine ◽

Michael Buckley ◽

...

Keyword(s):

Androgen Receptor ◽

Spinocerebellar Ataxia ◽

Sequence Variation ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 1 ◽

Machado Joseph Disease

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

Genetics Research International ◽

10.1155/2014/210418 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 2

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.

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Children with type 1 diabetes of early age at onset – immune and metabolic phenotypes

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0103 ◽

2019 ◽

Vol 32 (9) ◽

pp. 935-941

Author(s):

Madalena Sales Luis ◽

Margarida Alcafache ◽

Sara Ferreira ◽

Ana Laura Fitas ◽

Joana Simões Pereira ◽

...

Keyword(s):

Type 1 Diabetes ◽

Age At Onset ◽

Disease Onset ◽

Inverse Correlation ◽

Early Age ◽

Insulin Requirements ◽

Age Related ◽

One Year ◽

Immune Imbalance

Abstract Objectives We aimed to evaluate children with type 1 diabetes (T1D) with early age at onset (EAO) for clinical, immune and metabolic features in order to identify age-related disease phenotypes. Methods Comparative study of two groups of T1D children: EAO (≤5 years) and later age at onset (LAO; >5 years), regarding the presence of other autoimmune (AI) diseases, diabetes ketoacidosis and immunologic profile at onset and metabolic data 1 year after diagnosis. Statistical analysis was performed with significance set for p < 0.05. Results The study included 137 children (EAO = 52, mean age 3.6 ± 1.5 [mean ± standard deviation (SD)] and LAO = 85, mean age 10.4 ± 2.9). EAO was more associated with concomitant AI diseases (p = 0.032). Despite no differences in disease onset, EAO presented with lower C-peptide levels (p = 0.01) and higher absolute lymphocyte number (p < 0.0001), with an inverse correlation between these two variables (p = 0.028). Additionally, the EAO group had a higher frequency of serum detection of three antibodies (Abs) (p = 0.0008), specifically insulin Abs (p = 0.0001). One year after diagnosis, EAO had higher total daily insulin (TDI) dose (p = 0.008), despite similar hemoglobin A1c (HbA1c). Conclusions Our data show an association of EAO T1D with more AI diseases, higher number of Abs, lower initial insulin reservoir and higher insulin requirements 1 year after diagnosis. In this group, immune imbalance seems more evident and disease progression faster, probably reflecting distinct “immune environment” with different ages at disease onset. Further studies in the field of immunogenetics and immune tolerance are required, to improve patient stratification and find novel targets for therapeutic intervention.

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How Does Age at Onset Influence the Outcome of Autoimmune Diseases?

Autoimmune Diseases ◽

10.1155/2012/251730 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 13

Author(s):

Manuel J. Amador-Patarroyo ◽

Alberto Rodriguez-Rodriguez ◽

Gladis Montoya-Ortiz

Keyword(s):

Autoimmune Diseases ◽

Lupus Erythematosus ◽

Age At Onset ◽

Early Age ◽

Systemic Lupus ◽

Course Of Disease ◽

Mortality And Morbidity ◽

Time Period

The age at onset refers to the time period at which an individual experiences the first symptoms of a disease. In autoimmune diseases (ADs), these symptoms can be subtle but are very relevant for diagnosis. They can appear during childhood, adulthood or late in life and may vary depending on the age at onset. Variables like mortality and morbidity and the role of genes will be reviewed with a focus on the major autoimmune disorders, namely, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes mellitus (T1D), Sjögren's syndrome, and autoimmune thyroiditis (AITD). Early age at onset is a worst prognostic factor for some ADs (i.e., SLE and T1D), while for others it does not have a significant influence on the course of disease (i.e., SS) or no unanimous consensus exists (i.e., RA and MS).

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Spinocerebellar Ataxia Type 1 protein Ataxin-1 is signalled to DNA damage by Ataxia Telangiectasia Mutated kinase

10.1101/701953 ◽

2019 ◽

Author(s):

Celeste E. Suart ◽

Alma M. Perez ◽

Ismael Al-Ramahi ◽

Tamara Maiuri ◽

Juan Botas ◽

...

Keyword(s):

Dna Damage ◽

Spinocerebellar Ataxia ◽

Ataxia Telangiectasia ◽

Neurodegenerative Disorder ◽

Age At Onset ◽

Spinocerebellar Ataxia Type ◽

Ataxia Telangiectasia Mutated ◽

Spinocerebellar Ataxia Type 1 ◽

Polyglutamine Expansion

ABSTRACTSpinocerebellar Ataxia Type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the ataxin-1 protein. Recent genetic correlational studies have implicated DNA damage repair pathways in modifying the age at onset of disease symptoms in SCA1 and Huntington’s Disease, another polyglutamine expansion disease. We demonstrate that both endogenous and transfected ataxin-1 localizes to sites of DNA damage, which is impaired by polyglutamine expansion. This response is dependent on ataxia telangiectasia mutated (ATM) kinase activity. Further, we characterize an ATM phosphorylation motif within ataxin-1 at serine 188. We show reduction of the Drosophila ATM homolog levels in a ATXN1[82Q] Drosophila model through shRNA or genetic cross ameliorates motor symptoms. These findings offer a possible explanation as to why DNA repair was implicated in SCA1 pathogenesis by past studies. The similarities between the ataxin-1 and the huntingtin responses to DNA damage provide further support for a shared pathogenic mechanism for polyglutamine expansion diseases.

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

Neurological Sciences ◽

10.1007/s10072-019-04177-8 ◽

2019 ◽

Vol 41 (4) ◽

pp. 869-876 ◽

Cited By ~ 1

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.

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Towards genomic database of Alexander disease to identify variations modifying disease phenotype

Scientific Reports ◽

10.1038/s41598-019-51390-8 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Rei Yasuda ◽

Masakazu Nakano ◽

Tomokatsu Yoshida ◽

Ryuichi Sato ◽

Hiroko Adachi ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Late Onset ◽

Phenotypic Diversity ◽

Association Studies ◽

Age At Onset ◽

The Elderly ◽

Alexander Disease ◽

Candidate Gene Approach ◽

Intermediate Form ◽

Independent Population

Abstract Alexander disease (AxD) is an extremely rare neurodegenerative disorder caused by glial fibrillary acidic protein (GFAP) gene mutations. Compared with the cerebral type, which is characterized by infantile onset, the bulbospinal type and intermediate form are associated with a late onset, spanning from juveniles to the elderly, and more diverse clinical spectrum, suggesting the existence of factors contributing to phenotypic diversity. To build a foundation for future genetic studies of this rare disease, we obtained genomic data by whole exome-sequencing (WES) and DNA microarray derived from thirty-one AxD patients with the bulbospinal type and intermediate form. Using this data, we aimed to identify genetic variations determining the age at onset (AAO) of AxD. As a result, WES- or microarray-based association studies between younger (<45 years; n = 13)- and older (≥45 years; n = 18)-onset patients considering the predicted GFAP-mutation pathogenicity identified no genome-wide significant variant. The candidate gene approach identified several variants likely correlated with AAO (p < 0.05): GAN, SLC1A2, CASP3, HDACs, and PI3K. Although we need to replicate the results using an independent population, this is the first step towards constructing a database, which may serve as an important tool to advance our understanding of AxD.

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Functional Annotation of Small Noncoding RNAs Target Genes Provides Evidence for a Deregulated Ubiquitin-Proteasome Pathway in Spinocerebellar Ataxia Type 1

Journal of Nucleic Acids ◽

10.1155/2012/672536 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Stephan Persengiev ◽

Ivanela Kondova ◽

Ronald E. Bontrop

Keyword(s):

Spinocerebellar Ataxia ◽

Target Genes ◽

Neurodegenerative Disorder ◽

Noncoding Rnas ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Spinocerebellar Ataxia Type 1 ◽

Small Noncoding Rnas ◽

Ubiquitin Proteasome

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by the expansion of CAG repeats in the ataxin 1 (ATXN1) gene. In affected cerebellar neurons of patients, mutant ATXN1 accumulates in ubiquitin-positive nuclear inclusions, indicating that protein misfolding is involved in SCA1 pathogenesis. In this study, we functionally annotated the target genes of the small noncoding RNAs (ncRNAs) that were selectively activated in the affected brain compartments. The primary targets of these RNAs, which exhibited a significant enrichment in the cerebellum and cortex of SCA1 patients, were members of the ubiquitin-proteasome system. Thus, we identified and functionally annotated a plausible regulatory pathway that may serve as a potential target to modulate the outcome of neurodegenerative diseases.

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