Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16

Abstract

Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. A recent genome scan for genetic modifiers of age at onset of motor symptoms (AO) in HD suggests that one modifier may reside in the region close to the HD gene itself. We used data from 535 HD participants of the New England Huntington cohort Djoussé et al.Page 2 Neurogenetics. Author manuscript; available in PMC 2007 May 7. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript and the HD MAPS cohort to assess whether AO was influenced by any of the three markers in the 4p16 region: MSX1 (Drosophila homeo box homologue 1, formerly known as homeo box 7, HOX7), Δ2642 (within the HD coding sequence), and BJ56 (D4S127). Suggestive evidence for an association was seen between MSX1 alleles and AO, after adjustment for normal CAG repeat, expanded repeat, and their product term (model P value 0.079). Of the variance of AO that was not accounted for by HD and normal CAG repeats, 0.8% could be attributed to the MSX1 genotype. Individuals with MSX1 genotype 3/3 tended to have younger AO. No association was found between Δ2642 (P=0.44) and BJ56 (P=0.73) and AO. This study supports previous studies suggesting that there may be a significant genetic modifier for AO in HD in the 4p16 region. Furthermore, the modifier may be present on both HD and normal chromosomes bearing the 3 allele of the MSX1 marker.

Normal-repeat-length polyglutamine peptides accelerate aggregation nucleation and cytotoxicity of expanded polyglutamine proteins

“…Besides the nine proteins currently implicated in different polyGln expansion diseases (1), the human genome encodes many other proteins containing polyGln sequences of various repeat lengths (21)(22)(23). The analysis described here suggests that genetic modifiers of adult age-of-onset, predicted by human studies (28)(29)(30), may include variation in either the concentrations and͞or repeat lengths of some of these sequences to directly influence the aggressiveness of expanded repeat polyGln aggregation and disease. For example, the accelerating effect of normal-length polyGln sequences on polyGln aggregation nucleation and toxicity may help explain how overexpression of the polyGln-containing CREB-binding protein can in some animal and cellular models exacerbate expanded polyGln toxicity (Pedro Fernandez-Funez and Juan Botas, personal communication; and N.S., J.S.S., G.R.J., J.L.M.…”

NR1 Receptor Gene Variation is a Modifier of Age at Onset in Turkish Huntington’s Disease Patients

“…The alleles with up to 35 repeats are considered normal. However, repeats in the range of [29][30][31][32][33][34][35] have been shown to exhibit meiotic instability. Rare alleles with 36-39 repeats are in the reduced penetrance range, since some people with repeats in this range develop HD and others do not.…”

“…This has led to a search for genetic modiiers and environmental factors that inluence the AO. Diverse modiier candidate loci have been suggested to be associated with AO in HD such as GRIN, TP53, hCAD, UCHL1, BDNF, ASK1, and MTHFR [14,17,[23][24][25][26][27][28][29][30][31][32]. However, many reports from diferent research groups have been contradictory.…”

Genetic Modifiers of Neurological Disease

“…Identification of genetic modifiers is important for understanding the pathophysiology of inherited disease and may suggest genes and pathways that contribute to complex disease. Modifier loci have been mapped for several neurological diseases in human and mouse, including tremor, dystonia, epilepsy, motoneuron degeneration, and Huntington's disease [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Isolating modifier genes in humans is very challenging; however, genetic screens in model organisms can facilitate modifier identification and suggest candidate genes for follow-up study in human patients.…”