Interactions between PrP and Sho in health and disease are not yet clear, but these genetic data are consistent with an existing model that proposes a neuroprotective role for Sho.3 Our associations of a frameshift mutation, which may lead to a null allele, with vCJD, and *1 SPRN haplotypes with sCJD, are consistent with a direct or indirect interaction between proteins in the disease process. Here, SPRN is linked to variant Creutzfeldt-Jakob disease.