Workshop Reports

Genetic Modifiers of the HD Phenotype in Mice and Men

Reported by Lisa J. Bain.

Abstract:

Variation in age of onset of Huntington’s disease is highly correlated with CAG repeat length. However, when variation in repeat length is controlled for, variation in onset is still highly heritable, suggesting that other genetic factors modify the disease process. At a workshop sponsored by The Hereditary Disease Foundation in October 2002, 19 scientists met to discuss research aimed at identifying genetic modifiers in animal models and humans. Assays to screen for modifiers were described in Drosophila melanogaster, C. elegans, and mouse models. In C. elegans, one genetic modifier, dubbed pqe-1 (polyglutamine enhancer-1) has been identified in the laboratory of Anne Hart. Studies are underway to further characterize this low abundance but strongly enhancing protein; and to understand how it enhances polyglutamine toxicity. Searching for modifiers in mice is complicated by the variability in both background strains and the transgene itself, i.e., whether it is full length or truncated, the length of the CAG repeat, whether it is a knock-in or transgene, and which promoter is used. Two possible genetic modifiers were discussed: caspase-1 and Msh-2. In humans, investigators must determine which disease characteristics they wish to modify: age of onset, progression of disease, individual phenotypic features, or all of these characteristics. The next step will be to decide which approaches are most likely to be successful in assessing changes in these characteristics. Katrina Dipple described searching for genetic modifiers by looking for SNPs in candidate genes identified by understanding the basic biology of another rare disease, glycerol kinase deficiency. The workshop ended with more questions than answers, and with some clarification of what lies ahead.