A Missense Mutation in Canine CLN6 in an Australian Shepherd with Neuronal Ceroid Lipofuscinosis

Martin L Katz,Gary S Johnson,Fabiana H Farias,Douglas N Sanders,Dennis P O'Brien,Shahnawaz Khan,Rong Zeng

doi:10.1155/2011/198042

Abstract

The childhood neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative diseases that are progressive and ultimately fatal. An Australian Shepherd that exhibited a progressive neurological disorder with signs similar to human NCL was evaluated. The cerebral cortex, cerebellum, and retina were found to contain massive accumulations of autofluorescent inclusions characteristic of the NCLs. Nucleotide sequence analysis of DNA from the affected dog identified a T to C variant (c.829T>C) in exon 7 of CLN6. Mutations in the human ortholog underlie a late-infantile form of NCL in humans. The T-to-C transition results in a tryptophan to arginine amino acid change in the predicted protein sequence. Tryptophans occur at homologous positions in the CLN6 proteins from all 13 other vertebrates evaluated. The c.829T>C transition is a strong candidate for the causative mutation in this NCL-affected dog. Dogs with this mutation could serve as a model for the analogous human disorder.

Highlights

The neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative disorders that occur in humans and a number of other mammals, including dogs, cats, sheep, mice, and cattle [1, 2]
We were only able to amplify CLN6 exons 2, 3, 5, 6, and 7 from the DNA recovered from paraffin blocks containing tissue from the affected Australian Shepherd
Of the NCLs, the ultrastructural appearance of the brain storage material most closely resembled that of storage bodies that accumulate in the brain as a result of mutations in CLN6 [8]

Summary

Introduction

The neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative disorders that occur in humans and a number of other mammals, including dogs, cats, sheep, mice, and cattle [1, 2]. NCLs have been reported in a large number of dog breeds including Border Collies, English Setters, American Bulldogs, Dachshunds, Polish Lowland Sheepdogs, and Tibetan Terriers [3]. For five breeds (Border Collies, English Setters, American Bulldogs, Dachshunds, and Tibetan Terriers), the causative mutations have been identified, all of which are associated with an autosomal recessive mode of inheritance. These mutations all occur in orthologs of genes that contain mutations responsible for specific forms of human NCL or a similar disorder. Genomic DNA was recovered from paraffin blocks from the dog’s tissues and analyzed to determine whether CLN6 contained any potential disease-causing mutations

Methods

Results

Discussion

Conclusion