Genetic analysis of candidate genes modifying the age-at-onset in Huntington’s disease

Abstract

The expansion of a polymorphic CAG repeat in the HD gene encoding huntingtin has been identified as the major cause of Huntington's disease (HD) and determines 42-73% of the variance in the age-at-onset of the disease. Polymorphisms in huntingtin interacting or associated genes are thought to modify the course of the disease. To identify genetic modifiers influencing the age at disease onset, we searched for polymorphic markers in the GRIK2, TBP, BDNF, HIP1 and ZDHHC17 genes and analysed seven of them by association studies in 980 independent European HD patients. Screening for unknown sequence variations we found besides several silent variations three polymorphisms in the ZDHHC17 gene. These and polymorphisms in the GRIK2, TBP and BDNF genes were analysed with respect to their association with the HD age-at-onset. Although some of the factors have been defined as genetic modifier factors in previous studies, none of the genes encoding GRIK2, TBP, BDNF and ZDHHC17 could be identified as a genetic modifier for HD.

Mutant huntingtin Impairs the Post-Golgi Trafficking of Brain-Derived Neurotrophic Factor But Not Its Val66Met Polymorphism

“…However, it has been reported recently that there is no evidence of association between Met-BDNF and the age at onset of HD (Di Maria et al, 2006;Metzger et al, 2006), which could be related to the different origin population and/or size sample. In fact, differences in the influence of Met-BDNF has been described in different neurological disorders depending on the population analyzed (Ribases et In conclusion, our findings involve htt in post-Golgi transport regulation and that mhtt differently affects the post-Golgi transport of Val-BDNF and Met-BDNF, affecting more severely the regulated release of Val-BDNF compared with Met-BDNF.…”

A systematic review of the intergenerational aspects and the diverse genetic profiles of Huntington's disease

“…On the other hand, a study with 980 individuals in European countries provided strong evidence for an association of the size of the CAG and CCG repeats with age at onset of HD (Metzger et al, 2006).…”

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

“…There is a signiicant inverse correlation between the AO and the CAG repeat length [11,12]. However, the number of the CAG repeats does not allow an accurate prediction of AO, only 30-70% of the variance in AO can be explained by the repeat size alone [13][14][15][16][17][18][19][20]. The AO varies signiicantly among individuals with the same CAG size, and even monozygotic HD twins may show phenotypic discordance for the disease [21,22].…”