Neuronal Ceroid Lipofuscinosis (NCL) in Golden Retrievers
Neuronal ceroid lipofuscinosis results from the accumulation of granules in the neurons of the brain and spinal cord. This progressive neurological disorder manifests as behavioral changes coupled with a loss of coordination and blindness.
Phenotype: Neuronal ceroid lipofuscinosis is characterized by a progressive loss of coordination, blindness and behavioral changes beginning at 1.5 to 2 years of age.
Breeds appropriate for testing: Golden Retriever and Golden Retriever crosses
Explanation of Results:
Dogs with N/N genotype do not have the variant associated with neuronal ceroid lipofuscinosis found in Golden Retrievers.
Dogs with N/CL genotype are carriers of the neuronal ceroid lipofuscinosis variant found in Golden Retrievers, but will not develop neuronal ceroid lipofuscinosis. If two carriers are mated, approximately 25% of the puppies are predicted to develop the disease and 50% are predicted to be carriers.
Dogs with CL/CL genotype are homozygous for the neuronal ceroid lipofuscinosis variant found in Golden Retrievers and are expected to develop the disease.
Neuronal ceroid lipofuscinosis (NCL) is a group of progressive degenerative diseases of the central nervous system. Signs of disease in affected dogs begin between one and two years of age and include behavior issues such as: anxiety, constant circling, aggression, compulsive behaviors, and loss of learned skills. Additional neurological symptoms include: tremors, ataxia (lack of coordination), localized and generalized seizures, and visual impairment occasionally to the point of blindness. The progressive nature of this disease often results in euthanasia of the affected dog by 3 years, due to the poor quality of life.
In Golden Retrievers, a two base pair deletion in the ceroid lipofuscinosis neuronal protein 5 (CLN5) gene is thought to cause this disease. This two base pair deletion (denoted as c.934_935delAG) causes a frameshift in the gene product that results in a shortened protein (p.E312Vfs*6). The shortened protein is predicted to lack 39 amino acids including those that are essential for proper processing and trafficking of the protein. Specifically, there are several glycosylation sites in this protein that are required for it to be transported to the correct part of the cell where it normally functions to degrade proteins (lysosome). It is hypothesized that lack of normal CLN5 results in abnormal accumulation of storage material particularly in the cells of the central nervous system, leading to disease.
NCL is a recessive trait, meaning two copies of the variant must be present, one inherited from each parent, for the dog to show symptoms. Based on the study that identified this mutation, the allele frequency for the CL allele is rare in the Golden Retriever population (less than 1%). If only one copy is inherited (from either parent), no symptoms will be observed but the animal is a carrier and can pass the variant to its offspring. If two carriers are bred together, each puppy born has a 25% chance of developing NCL. Breeders can use the results of this test to assist with mate selection. Dogs who genotype CL/CL should be clinically evaluated.
Note: This test is specific for the CLN5 autosomal recessive neuronal ceroid lipofuscinosis variant present in the Golden Retriever. This assay does not detect the neuronal ceroid lipofuscinosis variants in other breeds nor does it detect the CLN5 variants in Border Collies and Australian Cattle Dogs.
Neuronal Ceroid Lipofuscinosis in Golden Retrievers (CL)
Normal. Dog does not have the variant associated with neuronal ceroid lipofuscinosis found in Golden Retrievers.
Carrier. Dog has one copy of the variant associated with neuronal ceroid lipofuscinosis found in Golden Retrievers.
Affected. Dog has two copies of the variant associated with neuronal ceroid lipofuscinosis found in Golden Retrievers and will likely develop the disease.
Gilliam, D., Kolicheski, A., Johnson, G.S., Mhlanga-Mutangadura, T., Taylor, J.F., Schnabel, R.D., & Katz, M.L. (2015). Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5. Molecular Genetics and Metabolism, 115(2-3), 101-109. doi: 10.1016/j.ymgme.2015.04.001