A heritable neurodegenerative disease of English Setters has long been studied as a model of human neuronal ceroid-lipofuscinosis (NCL). Megablast searches of the first build of the canine genome for potential causative genes located the CLAW gene near the q telomere of canine chromosome 37, close to a marker previously linked to English Setter NCL. Sequence analysis of the coding region from affected dogs revealed a T-to-C transition in the CLN8 gene that predicts a p.L164P missense mutation. Leucine 1644 is conserved in four other mammalian species. The C allele co-segregated with the disease phenotype in a two generation English Setter family in a pattern consistent with autosornal recessive inheritance. All four NCL-affected family members were C/C homozyrMes and all four obligate carriers were C/T heterozygotes; whereas. 103 unrelated dogs were all T/T homozygotes. These findings indicate that the CLN8 T-to-C transition is the likely cause of English Setter NCL. (C) 2004 Elsevier Inc. All rights reserved.