Exploring Genetic Factors Involved in Huntington Disease Age of Onset: E2F2 as a New Potential Modifier Gene

Valcárcel-Ocete, Leire; Alkorta‐Aranburu, Gorka; Iriondo, Mikel; Fullaondo, Asier; García-Barcina, María; Fernández-García, José Manuel; Lezcano-García, Elena; Losada-Domingo, José María; Ruiz-Ojeda, Javier; Arcaya, Amaia Álvarez de; Pérez-Ramos, José María; Roos, Raymund A.C.; Nielsen, Jørgen E.; Saft, Carsten; Zubiaga, Ana M.; Aguirre, A.

doi:10.1371/journal.pone.0131573

Cited by 11 publications

(5 citation statements)

References 76 publications

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“…Experimental studies have shown that Huntingtin (HTT) binds to ATF7IP, a SETDB1 regulator, resulting in low H3K9me3 levels, whereas loss of HTT upregulates H3K9me3 marks mainly on genes affecting neuronal differentiation. Interestingly, genetic variations of ATF7IP seem to correlate with HD’s age of onset [ 140 ], adding ATF7IP to the list of potential targets for reducing H3K9me3 levels upregulated by the mutant HTT [ 141 ].…”

Section: Setdb1 Connection To Other Diseasesmentioning

confidence: 99%

Structure, Activity and Function of the SETDB1 Protein Methyltransferase

Markouli

Strepkos

Piperi

2021

Life

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The SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1) is a prominent member of the Suppressor of Variegation 3–9 (SUV39)-related protein lysine methyltransferases (PKMTs), comprising three isoforms that differ in length and domain composition. SETDB1 is widely expressed in human tissues, methylating Histone 3 lysine 9 (H3K9) residues, promoting chromatin compaction and exerting negative regulation on gene expression. SETDB1 has a central role in normal physiology and nervous system development, having been implicated in the regulation of cell cycle progression, inactivation of the X chromosome, immune cells function, expression of retroelements and formation of promyelocytic leukemia (PML) nuclear bodies (NB). SETDB1 has been frequently deregulated in carcinogenesis, being implicated in the pathogenesis of gliomas, melanomas, as well as in lung, breast, gastrointestinal and ovarian tumors, where it mainly exerts an oncogenic role. Aberrant activity of SETDB1 has also been implicated in several neuropsychiatric, cardiovascular and gastrointestinal diseases, including schizophrenia, Huntington’s disease, congenital heart defects and inflammatory bowel disease. Herein, we provide an update on the unique structural and biochemical features of SETDB1 that contribute to its regulation, as well as its molecular and cellular impact in normal physiology and disease with potential therapeutic options.

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Section: Setdb1 Connection To Other Diseasesmentioning

confidence: 99%

Structure, Activity and Function of the SETDB1 Protein Methyltransferase

Markouli

Strepkos

Piperi

2021

Life

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“…The lack of replication of candidate modifiers of HD has been reported before. For example, candidate studies suggested modification of HD by ADORA2A , 60 , 61 ATG7 , 62 BDNF , 63 GRIK2 , 64 GRIN2A , 64-66 GRIN2B , 64 , 65 HAP1 , 67 HIP1 , 64 LINC01559 , 64 NPY2R , 68 PPARGC1A 69-72 and UCHL1 . 73 However, none of these genes generated significant onset modification signals in our large scale unbiased genetic analysis.…”

Section: Discussionmentioning

confidence: 99%

Modification of Huntington’s disease by short tandem repeats

Hong,

Ramos,

Aziz

et al. 2024

Brain Communications

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Expansions of glutamine-coding CAG trinucleotide repeats cause a number of neurodegenerative diseases, including Huntington's disease (HD) and several of the spinocerebellar ataxias (SCAs). In general, age-at-onset of the polyglutamine diseases is inversely correlated with the size of the respective inherited expanded CAG repeat. Expanded CAG repeats are also somatically unstable in certain tissues, and age-at-onset of HD corrected for individual HTT CAG repeat length (i.e., residual age-at-onset), is modified by repeat instability-related DNA maintenance/repair genes as demonstrated by recent genome-wide association studies (GWAS). Modification of one polyglutamine disease (e.g., HD) by the repeat length of another (e.g., ATXN3, CAG expansions in which cause SCA3) has also been hypothesized. Consequently, we determined whether age-at-onset in HD is modified by the CAG repeats of other polyglutamine disease genes. We found that the CAG measured repeat sizes of other polyglutamine disease genes were polymorphic in HD participants but did not influence HD age-at-onset. Additional analysis focusing specifically on ATXN3 in a larger sample set (n = 1,388) confirmed the lack of association between HD residual age-at-onset and ATXN3 CAG repeat length. Additionally, neither our HD onset modifier GWAS single nucleotide polymorphism (SNP) data nor imputed short tandem repeat (STR) data supported involvement of other polyglutamine disease genes in modifying HD. By contrast, our GWAS based on imputed STRs revealed significant modification signals for other genomic regions. Together, our STR GWAS show that modification of HD is associated with STRs that do not involve other polyglutamine disease-causing genes, refining the landscape of HD modification and highlighting the importance of rigorous data analysis, especially in genetic studies testing candidate modifiers.

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“…European Huntington’s Disease Network’s (EHDN) REGISTRY project provided data on 1,011 HD individuals. For this study, we gathered information on mAO [ 3 ], sex and age at the time of data collection of 630 European adult-onset HD patients with CAGexp ranging between 40 and 50, with known AHT status (86 hypertensives vs . 544 normotensives) and with AHT onset date available in the REGISTRY dataset.…”

Section: Methodsmentioning

confidence: 99%

“…544 normotensives) and with AHT onset date available in the REGISTRY dataset. The 40–50 CAGexp range was selected to avoid the inclusion of juvenile-onset HD cases and thus, the introduction of errors in the regression analysis [ 3 – 5 ]. Furthermore, 40–50 CAGexp was the repeat range of hypertensive patients in our sample.…”

Section: Methodsmentioning

confidence: 99%

Does arterial hypertension influence the onset of Huntington's disease?

et al. 2018

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Huntington’s disease (HD) age of onset (AO) is mainly determined by the length of the CAG repeat expansion in the huntingtin gene. The remaining AO variability has been attributed to other little-known factors. A factor that has been associated with other neurodegenerative diseases is arterial hypertension (AHT). The aim of this study is to evaluate the contribution of AHT to the AO of HD. We used data from a cohort of 630 European HD patients with adult onset collected by the REGISTRY project of the European Huntington’s Disease Network. Multiple linear regression and ANOVA, controlling for the CAG repeat number of the expanded allele (CAGexp) of each patient, were performed to assess the association between the AHT condition and the AO of the motor symptoms (mAO). The results showed a significant association between AHT and mAO, especially when we only considered the patients diagnosed with AHT prior to manifesting any HD signs (pre-HD AHT). Remarkably, despite the low number of cases, those patients developed motor symptoms 5–8 years later than normotensive patients in the most frequent CAGexp range (40–44). AHT is an age-related condition and consequently, the age of the patient at the time of data collection could be a confounder variable. However, given that most pre-HD AHT patients included in our study had started treatment with antihypertensive drugs prior to the onset of HD, and that antihypertensive drugs have been suggested to confer a neuroprotective effect in other neurodegenerative diseases, raises the interest in elucidating the impact of AHT and/or AHT treatment in HD age of onset in further studies. A confirmation of our results in a larger sample set would open the possibility to significantly improve HD management.

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Exploring Genetic Factors Involved in Huntington Disease Age of Onset: E2F2 as a New Potential Modifier Gene

Cited by 11 publications

References 76 publications

Structure, Activity and Function of the SETDB1 Protein Methyltransferase

Structure, Activity and Function of the SETDB1 Protein Methyltransferase

Modification of Huntington’s disease by short tandem repeats

Does arterial hypertension influence the onset of Huntington's disease?

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