title: A missense mutation (c.184C>T) in ovine CLN6 causes neuronal ceroid lipofuscinosis in Merino sheep whereas affected South Hampshire sheep have reduced levels of CLN6 mRNA.
abstract: The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are a group of fatal recessively inherited neurodegenerative diseases of humans and animals characterised by common clinical signs and pathology. These include blindness, ataxia, dementia, behavioural changes, seizures, brain and retinal atrophy and accumulation of fluorescent lysosome derived organelles in most cells. A number of different variants have been suggested and seven different causative genes identified in humans (CLN1, CLN2, CLN3, CLN5, CLN6, CLN8 and CTSD). Animal models have played a central role in the investigation of this group of diseases and are extremely valuable for developing a better understanding of the disease mechanisms and possible therapeutic approaches. Ovine models include flocks of affected New Zealand South Hampshires and Borderdales and Australian Merinos. The ovine CLN6 gene has been sequenced in a representative selection of these sheep. These investigations unveiled the mutation responsible for the disease in Merino sheep (c.184C>T; p.Arg62Cys) and three common ovine allelic variants (c.56A>G, c.822G>A and c.933_934insCT). Linkage analysis established that CLN6 is the gene most likely to cause NCL in affected South Hampshire sheep, which do not have the c.184C>T mutation but show reduced expression of CLN6 mRNA in a range of tissues as determined by real-time PCR. Lack of linkage precludes CLN6 as a candidate for NCL in Borderdale sheep.
authors.affiliation: Centre for Advanced Technologies in Animal Genetics and Reproduction (Reprogen), Faculty of Veterinary Science, The University of Sydney, PMB3, Camden, NSW, Australia. itammen@camden.usyd.edu.au
authors.forename: Imke
authors.initials: I
authors.lastname: Tammen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houweling
authors.forename: Tony
authors.initials: T
authors.lastname: Frugier
authors.forename: Nadia L
authors.initials: NL
authors.lastname: Mitchell
authors.forename: Graham W
authors.initials: GW
authors.lastname: Kay
authors.forename: Julie A L
authors.initials: JA
authors.lastname: Cavanagh
authors.forename: Roger W
authors.initials: RW
authors.lastname: Cook
authors.forename: Herman W
authors.initials: HW
authors.lastname: Raadsma
authors.forename: David N
authors.initials: DN
authors.lastname: Palmer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000662:veterinary*; D012333:RNA, Messenger / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012756:Sheep; D012757:Sheep Diseases / Q000235:genetics*; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; D000091346:Tripeptidyl-Peptidase 1; C000717267:TPP1 protein, human