Ovine neuronal ceroid lipofuscinosis: a large animal model syntenic with the human neuronal ceroid lipofuscinosis variant CLN6.

Abstract

The neuronal ceroid lipofuscinoses (NCLs) are a group ofinherited degenerative neurological diseases affecting children. A number of non-allelic variants have been identified within the human population and the genes for some ofthese have recently been identified. The underlying mechanism for the neuropathology remains an enigma; however, pioneering studies with the naturally occurring ovine model (OCL) have led to the proposal that these diseases represent lesions in specific hydrophobic protein degradation pathways. In this study, we show linkage between OCL and microsatelilite markers on OAR 7q13-15. Using interspecies chromosome painting we establish that OAR 7ql3-15 is syntenic with human chromosome 15q21-23, the region which was recently defined as the location of a newly identified late infantile variant (CLN6). We propose that our ovine model represents a mutation in the gene orthologous to that mutated in the human late infantile variant CLN6. The ovine linkage flock, consisting of 56 families, represents a powerful resource for positional cloning of this NCL gene. The availability of such a large animal model will have important implications for experimentation in downstream corrective therapies.

A mouse gene knockout model for juvenile ceroid-lipofuscinosis (batten disease)

“…A recent analysis has, however, ruled out a defect in the canine CLN3 gene homolog as the cause of the English Setter disease (Shibuya et al, 1998). Defects in homologs of the CLN3 gene have also been ruled out as the causes of Batten-like diseases in sheep and mice (Broom et al, 1998;Messer et al, 1992). Therefore, the homozygous Cln3 knockout mice represent the only known animal model with a defect in the gene that is homologous to that which is defective in humans with Batten disease.…”

The development and characterisation of complex ovine neuron cultures from fresh and frozen foetal neurons

“…Sheep have a gyrencephalic human-like brain, large enough to provide a substantial number of cells, are easy to husband and have low maintenance requirements. More specific reasons to study sheep neurons include neurological diseases in sheep of interest to humans, notably Scrapie and the inherited lysosomal storage disease, ovine CLN6 ceroid lipofuscinosis, studied as a model of the fatal neurodegenerative human neuronal ceroid lipofuscinoses (Batten disease) (Jolly et al, 1989;Palmer et al, 1992;Jolly and Palmer, 1995;Broom et al, 1998).…”

Lysine 43 Is Trimethylated in Subunit c from Bovine Mitochondrial ATP Synthase and in Storage Bodies Associated with Batten Disease

“…Each form is caused by mutations in specific genes. A form in sheep is syntenic with the human CLN6 1 (early juvenile or late infantile variant) disease (11)(12)(13). Specific lysosomal storage of subunit c has been demonstrated by protein sequencing of bodies from these sheep and of human samples associated with the CLN2 (late infantile), CLN3 (juvenile), (14 -16), CLN5, and CLN8 human forms (17,18).…”