NCL 8 in English Setters

Neuronal ceroid lipofuscinosis type 8 (NCL 8) is a neurodegenerative disorder which affects people, dogs and other animals (e.g. cattle, sheep, horses). In some animals the causal mutation leading to NCL has not been described yet. In connection with NCL in animals and people mutations in six different genes CLN 1,2,3,4,5,6,8 (Daly et al. 1998, Gupta et al. 2001) have been described for now. Each mutation in the given gene causes a unique form of NCL.

NCL disease in English setters was first described in 1950 by Norwegian veterinarian Nils Koppang. In the breed of English setter causal mutation c.491T>C was found in CLN8 gene. It is a single-base substitution which leads to p.L164P substitution in CLN8 protein (Katz et al. 2005). Leucine in position 164 is highly preservered amino acid in mammals. This mutation was found in all NCL affected individuals and was not found in 103 healhty controls.

Typical for neuronal ceroid lipofuscinosis is accumulating of lipopigments (ceroid and lipofuscin) in lysosomes. Clinical symptoms can be observed in English setters quite early, around 15th-18th month of a dog age. The beginning and clinical course of the disease vary greatly and are very individual. The rate of neurodegeneration increases together with the age, with psychical abnormalities and ataxy usually developing in all affected dogs. Changes in walking and posture can be observed - stumbling and acampsia. Affected animals usually have abnormal EEG and MRI response before first symptoms appears. Accompanying symptom is damaged retina. Death usually occurs between 19th-27th months of age.

Clinical symptoms in English setters are similar to NCL symptoms in border collies (causal mutation was found in CLN5 gene (Melville 2005)).

NCL is inherited autosomally recessively which means that the disease develops only in those dogs who inherit mutated allele from both parents. Carriers of mutated allele (heterozygotes) are clinically healthy but transmit the mutation on their descendants. In case of mating two heterozygous dogs there is a theoretical chance that 25% of descendants will be absolutely healthy, 50% will be carriers a 25% will inherit from both parents mutated allele and therefore will be NCL affected.

References:
M.L. Katz, et al., A mutation in the CLN8 gene in English setter dogs with neuronal ceroid-lipofuscinosis, Biochem. Biophys. Res. Commun.327 (2005) 541- 547.
Melville SA, Wilson CL, Chiang CS, Studdert VP, Lingaas F, Wilton AN. A mutation in canine CLN5 causes neuronal ceroid lipofuscinosis in Border collie dogs. Genomics. 2005 Sep;86(3):287-94
M.J. Daly, et al., GENEHUNTER 2.0-A complete linkage analysis system, Am. J. Hum. Genet. Suppl. 63 (1998) A286.
V.P. Studdert, R.W. Mitten, Clinical features of ceroid lipofuscinosis in Border collie dogs, Aust. Vet. J. 68 (1991) 137- 140.
P. Gupta, et al., Disruption of PPT1 or PPT2 causes neuronal ceroid lipofuscinosis in knockout mice, Proc. Natl. Acad. Sci. USA 98 (2001)13566-13571.