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.

The neuronal ceroid lipofuscinoses: the same, but different?

“…In this respect, large animal models of NCL are particularly informative [18], as we can examine the onset and progression of the same neuropathological features we have seen in mice. Making such comparisons between mice and sheep that model the same form of NCL [17,39,40] reveals that, although similar phenotypes are evident, they are much more severe in sheep and in the corresponding human disease.…”

“…In addition to mice, these models include a diverse series of large-animal species [18], with dog and sheep models the best characterized and most widely used. The larger and more complex brain of these species has particular advantages for modelling human disease and for addressing the translation of experimental therapies into a clinical setting.…”

Lentiviral-Mediated Gene Transfer to the Sheep Brain: Implications for Gene Therapy in Batten Disease

“…All animal work was approved by the Lincoln University Animal Ethics Committee and complied with the New Zealand Animal Welfare Act, 1999. Homozygous affected South Hampshire lambs were generated by mating heterozygous ewes to homozygous affected rams, and the genotype was determined using a discriminatory c.822G>A polymorphism in the CLN6 gene (Tammen et al, 2006). At the time of vector injection, the sheep were 8 months of age and in good health.…”

“…Two naturally occurring forms of CLN5 and CLN6 NCL have been found in sheep, and well established flocks are available for model studies ( Jolly et al, 2002;Tammen et al, 2006;Frugier et al, 2008). Both are classical subunit c of mitochondrial ATP synthase-storing forms of NCL (Chen et al, 2004;Frugier et al, 2008).…”

Animal models for human disease – reflections from an animal researcher’s perspective

“…My own research focuses on sheep and cattle that are affected with NCL (Houweling et al2006;Tammen et al 2006;Frugier et al 2008). Initially the research concentrated on the identification of disease-causing mutations in these animals for diagnostic purposes in livestock industries.…”