Neuronal ceroid lipofuscinosis 3, NCL3 (CLN3-related)

Gene: CLN3

Transmission: Autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease.  Both parents of an affected animal must be carriers of at least one copy of the mutation.  Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Deletion, CLN3 gene: c.1106 del.G, p.(Pro369Arg frameshift STOP 8), exon16, Chr.25.

Medical system: Ocular, lysosomal storage disease

Breed: Herford

Age of onset of symptoms: By one year of age.

Thirteen adult Herford animals were diagnosed with blindness with no other medical symptoms.  A pedigree analysis revealed a fourth-generation common ancestor, suggesting a genetic recessive cause of the blindness.  Molecular studies revealed a mutation in the CLN3 gene that was homozygous in all affected animals and heterozygous in parents of the affected animals.  The CLN3 gene codes for a membrane transporter protein important in lysosomal function and in particular is involved in photoreceptor recycling in retinal cells.  Mutations in the CLN3 gene are the cause of neuronal ceroid lipofuscinosis 3 (NCL3) in humans, referred to as Batten disease, with symptoms that include retinal blindness.  A diagnosis of NCL3 was made for the blind Herford animals.  In contrast to NCL3 in humans, the blind cattle showed no additional neurological signs such as ataxia or convulsions, nor did they have lipofuscinosis deposits in retinal tissue.  In a survey of 462 Herford animals, 69 animals were identified as carriers representing a carrier frequency of 15%.  A DNA test is available to help breeders and veterinarians to now remove this mutation from their stock.  Care should be exercised in doing this over several generations so as not to cause genetic bottlenecks resulting in additional genetic problems.

References:

OMIA link: [2432-9913]

Reith RR, Batt MC, Fuller AM, et al. (2024) A recessive CLN3 variant is responsible for delayed-onset retinal degeneration in Hereford cattle. J Vet Diagn Invest 36:438-446.  [pm/38516801]

With contributions by: Edouard Doyon and Aly Shalaby, Class of 2030, Veterinary Faculty of Medicine, University of Montreal.  (Translation: DWS).