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

Brahim, Dorra H’mida-Ben; Chourabi, Marwa; Amor, Sana Ben; Harrabi, Imed; Trabelsi, Saoussen; Haddaji-Mastouri, Marwa; Gribaa, Moez; Sassi, Sihem; Gahbiche, Fatma Ezzahra; Lamouchi, T.; Mougou-Zereli, Soumaya; Ammou, Sofiane Ben; Saâd, Ali

doi:10.1155/2014/210418

Cited by 4 publications

(10 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Polyglutamine diseases share a similar genetic basis and their phenotypes, such as AAO, are affected by CAG repeat variations in the normal range in polyQ genes other than the causative gene ( Pulst et al, 2005 ; De Castilhos et al, 2014 ; Hmida-Ben Brahim et al, 2014 ; Tezenas et al, 2014 ; Chen et al, 2016 ; Stuitje et al, 2017 ). The causative polyQ genes are thought to modulate protein interactions through the role of CAG tracts in stabilizing protein interactions ( Schaefer et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In HD and SCAs, longer CAG repeat lengths in the causative polyQ genes are associated with an earlier age-at-onset (AAO) ( Hmida-Ben Brahim et al, 2014 ; Tezenas et al, 2014 ). In HD, up to 75% of the variability in AAO can be explained by the HTT CAG repeat length ( Hmida-Ben Brahim et al, 2014 ), while in SCA1, SCA2, SCA3, SCA6, and SCA7, the CAG repeat in the causative gene explains between 32 and 80% of the AAO variability ( Tezenas et al, 2014 ). There is also evidence suggesting that, in addition to the expanded CAG repeat length in the causative gene, the normal CAG repeat lengths in other non-causative polyQ genes affect the AAO in HD and SCA’s ( Pulst et al, 2005 ; De Castilhos et al, 2014 ; Hmida-Ben Brahim et al, 2014 ; Tezenas et al, 2014 ; Chen et al, 2016 ; Stuitje et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…In HD, up to 75% of the variability in AAO can be explained by the HTT CAG repeat length ( Hmida-Ben Brahim et al, 2014 ), while in SCA1, SCA2, SCA3, SCA6, and SCA7, the CAG repeat in the causative gene explains between 32 and 80% of the AAO variability ( Tezenas et al, 2014 ). There is also evidence suggesting that, in addition to the expanded CAG repeat length in the causative gene, the normal CAG repeat lengths in other non-causative polyQ genes affect the AAO in HD and SCA’s ( Pulst et al, 2005 ; De Castilhos et al, 2014 ; Hmida-Ben Brahim et al, 2014 ; Tezenas et al, 2014 ; Chen et al, 2016 ; Stuitje et al, 2017 ). For example, clinical observations show that the AAO in HD is not only affected by the expanded CAG repeat length in HTT , but also by the normal CAG repeat length in ATN1 and ATXN1 negatively affecting the AAO ( Hmida-Ben Brahim et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…There is also evidence suggesting that, in addition to the expanded CAG repeat length in the causative gene, the normal CAG repeat lengths in other non-causative polyQ genes affect the AAO in HD and SCA’s ( Pulst et al, 2005 ; De Castilhos et al, 2014 ; Hmida-Ben Brahim et al, 2014 ; Tezenas et al, 2014 ; Chen et al, 2016 ; Stuitje et al, 2017 ). For example, clinical observations show that the AAO in HD is not only affected by the expanded CAG repeat length in HTT , but also by the normal CAG repeat length in ATN1 and ATXN1 negatively affecting the AAO ( Hmida-Ben Brahim et al, 2014 ). The observation that the number of CAG repeats in multiple polyQ genes can affect the AAO in HD or SCAs suggests that polyQ gene products are functionally interacting.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Co-expression Patterns between ATN1 and ATXN2 Coincide with Brain Regions Affected in Huntington’s Disease

Keo

Aziz

Dzyubachyk

et al. 2017

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Cytosine-adenine-guanine (CAG) repeat expansions in the coding regions of nine polyglutamine (polyQ) genes (HTT, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, ATN1, AR, and TBP) are the cause of several neurodegenerative diseases including Huntington’s disease (HD), six different spinocerebellar ataxias (SCAs), dentatorubral-pallidoluysian atrophy, and spinobulbar muscular atrophy. The expanded CAG repeat length in the causative gene is negatively related to the age-at-onset (AAO) of clinical symptoms. In addition to the expanded CAG repeat length in the causative gene, the normal CAG repeats in the other polyQ genes can affect the AAO, suggesting functional interactions between the polyQ genes. However, there is no detailed assessment of the relationships among polyQ genes in pathologically relevant brain regions. We used gene co-expression analysis to study the functional relationships among polyQ genes in different brain regions using the Allen Human Brain Atlas (AHBA), a spatial map of gene expression in the healthy brain. We constructed co-expression networks for seven anatomical brain structures, as well as a region showing a specific pattern of atrophy in HD patients detected by magnetic resonance imaging (MRI) of the brain. In this HD-associated region, we found that ATN1 and ATXN2 were co-expressed and shared co-expression partners which were enriched for DNA repair genes. We observed a similar co-expression pattern in the frontal lobe, parietal lobe, and striatum in which this relation was most pronounced. Given that the co-expression patterns for these anatomical structures were similar to those for the HD-associated region, our results suggest that their disruption is likely involved in HD pathology. Moreover, ATN1 and ATXN2 also shared many co-expressed genes with HTT, the causative gene of HD, across the brain. Although this triangular relationship among these three polyQ genes may also be dysregulated in other polyQ diseases, stronger co-expression patterns between ATN1 and ATXN2 observed in the HD-associated region, especially in the striatum, may be more specific to HD.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Co-expression Patterns between ATN1 and ATXN2 Coincide with Brain Regions Affected in Huntington’s Disease

Keo

Aziz

Dzyubachyk

et al. 2017

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

Genetic Modifiers in H untington Disease

Clabough

Thompson

Lau

et al. 2016

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Huntington disease (HD) is a neurodegenerative disorder that is caused by an elongation of a normally occurring polyglutamine stretch within the huntingtin (HTT) protein. Since the mutation was first identified, multiple HD‐disease‐modifying gene candidates that can hasten or delay age of onset (AO) have been discovered. For the past several decades, candidate disease‐modifying genes have been chosen for investigation based on functionality or prior implication in the disease process. More recent approaches take advantage of newly available genomic‐wide assays to identify changes as small as single‐nucleotide polymorphisms (SNPs) in other parts of the genome. New information regarding disease‐modifying genes will continue to elucidate potential HD therapeutic candidates. Key Concepts Huntington disease is a neurodegenerative disease that results from excess CAG trinucleotide repeats in exon 1 of the HD gene, which is located in chromosome 4p16.3 and encodes the HTT protein. The number of CAG repeats in the HD gene inversely affects the age of onset (AO) in HD patients. Genetic modifiers are identified genes that have the ability to either hasten or delay AO of HD; however, the exact mechanism of many of these genes in association with the disease is unknown. HD genetic modifiers can significantly delay specific physiological HD symptoms, such as chorea. Some HD genetic modifiers can alter HD AO by up to 8 years. Genetic modifiers have been discovered by either the candidate approach, which involves exploring genes known to be associated with the HTT protein and genotyping any variants, or via a more unbiased genomic approach, which involves a broad search for genes that are not known to be associated with the HTT protein. Modifiers that affect HD do not necessarily need to be within close vicinity of the actual gene, but can be distributed elsewhere in the genome, even in noncoding regions.

show abstract

Investigation of the Influence of TBP CAG/CAA Repeats in Conjunction with HTT CAG Repeats on Huntington’s Disease Age at Onset in a Brazilian Sample

et al. 2022

View full text Add to dashboard Cite

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

Cited by 4 publications

References 14 publications

Co-expression Patterns between ATN1 and ATXN2 Coincide with Brain Regions Affected in Huntington’s Disease

Co-expression Patterns between ATN1 and ATXN2 Coincide with Brain Regions Affected in Huntington’s Disease

Genetic Modifiers in H untington Disease

Investigation of the Influence of TBP CAG/CAA Repeats in Conjunction with HTT CAG Repeats on Huntington’s Disease Age at Onset in a Brazilian Sample

Contact Info

Product

Resources

About