Population-specific genetic modification of Huntington's disease in Venezuela.

Modifiers of Mendelian disorders can provide insights into disease mechanisms and guide therapeutic strategies. A recent genome-wide association (GWA) study discovered genetic modifiers of Huntington's disease (HD) onset in Europeans. Here, we performed whole genome sequencing and GWA analysis of a Venezuelan HD cluster whose families were crucial for the original mapping of the HD gene defect. The Venezuelan HD subjects develop motor symptoms earlier than their European counterparts, implying the potential for population-specific modifiers. The main Venezuelan HD family inherits HTT haplotype hap.03, which differs subtly at the sequence level from European HD hap.03, suggesting a different ancestral origin but not explaining the earlier age at onset in these Venezuelans. GWA analysis of the Venezuelan HD cluster suggests both population-specific and population-shared genetic modifiers. Genome-wide significant signals at 7p21.2-21.1 and suggestive association signals at 4p14 and 17q21.2 are evident only in Venezuelan HD, but genome-wide significant association signals at the established European chromosome 15 modifier locus are improved when Venezuelan HD data are included in the meta-analysis. Venezuelan-specific association signals on chromosome 7 center on SOSTDC1, which encodes a bone morphogenetic protein antagonist. The corresponding SNPs are associated with reduced expression of SOSTDC1 in non-Venezuelan tissue samples, suggesting that interaction of reduced SOSTDC1 expression with a population-specific genetic or environmental factor may be responsible for modification of HD onset in Venezuela. Detection of population-specific modification in Venezuelan HD supports the value of distinct disease populations in revealing novel aspects of a disease and population-relevant therapeutic strategies.

The relationship between CAG repeat length and age of onset differs for Huntington's disease patients with juvenile onset or adult onset.

Age of onset for Huntington's disease (HD) varies inversely with the length of the disease-causing CAG repeat expansion in the HD gene. A simple exponential regression model yielded adjusted R-squared values of 0.728 in a large set of Venezuelan kindreds and 0.642 in a North American, European, and Australian sample (the HD MAPS cohort). We present evidence that a two-segment exponential regression curve provides a significantly better fit than the simple exponential regression. A plot of natural log-transformed age of onset against CAG repeat length reveals this segmental relationship. This two-segment exponential regression on age of onset data increases the adjusted R-squared values by 0.012 in the Venezuelan kindreds and by 0.035 in the HD MAPS cohort. Although the amount of additional variance explained by the segmental regression approach is modest, the two slopes of the two-segment regression are significantly different from each other in both the Venezuelan kindreds [F(2, 439) = 11.13, P= 2 x 10(-5)] and in the HD MAPS cohort [F(2, 688) = 38.27, P= 2 x 10(-16)]. In both populations, the influence of each CAG repeat on age of onset appears to be stronger in the adult-onset range of CAG repeats than in the juvenile-onset range.

Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse.

The CLN6 gene that causes variant late-infantile neuronal ceroid lipofuscinosis (vLINCL), a recessively inherited neurodegenerative disease that features blindness, seizures, and cognitive decline, maps to 15q21-23. We have used multiallele markers spanning this approximately 4-Mb candidate interval to reveal a core haplotype, shared in Costa Rican families with vLINCL but not in a Venezuelan kindred, that highlighted a region likely to contain the CLN6 defect. Systematic comparison of genes from the minimal region uncovered a novel candidate, FLJ20561, that exhibited DNA sequence changes specific to the different disease chromosomes: a G-->T transversion in exon 3, introducing a stop codon on the Costa Rican haplotype, and a codon deletion in exon 5, eliminating a conserved tyrosine residue on the Venezuelan chromosome. Furthermore, sequencing of the murine homologue in the nclf mouse, which manifests recessive NCL-like disease, disclosed a third lesion-an extra base pair in exon 4, producing a frameshift truncation on the nclf chromosome. Thus, the novel approximately 36-kD CLN6-gene product augments an intriguing set of unrelated membrane-spanning proteins, whose deficiency causes NCL in mouse and man.