Diffuse cystic renal dysplasia, hepatic fibrosis

Gene: INPP5E

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: Substitution, INPP5E gene (splicing error); c. 1572+5 G>A, intron9-10, chromosome 9.

Breed: Norwich Terrier

Medical systems: Renal, digestive.

Age of onset of symptoms: Lethal at or immediately after birth.

Three Norwich Terrier puppies from a related Finnish pedigree died at or shortly after birth.  Necropsy revealed a congenital developmental syndrome involving enlarged kidneys with dysplasia, diffuse renal cysts, and hepatic fibrosis.   DNA analysis identified a homozygous splicing error in the INPP5E gene, which was considered causative for the syndrome observed.  The INPP5E gene codes for an enzyme involved in maintaining primary cilia function.  Primary cilia are non-motile cilia found on the cell surface that are involved in increasing cell surface area, in signal transduction and in developmental decisions.  DNA from 480 additional Finnish Norwich Terriers was tested for the mutation, and a carrier frequency of 6.0% was determined.  DNA testing of 200 dogs from 69 additional breeds did not detect the mutation.  Further DNA studies are now warranted to determine if the mutation is found within the wider Norwich Terrier population.  Veterinarians and breeders of Norwich Terriers should be aware of this disease and mutation and should consider DNA testing of animals that are to be used for reproduction.

Additional genes involved with breed specific canine ciliopathies (genetic diseases of cilia) include:

Alaskan malamutes – NME5 gene, OMIA link: [2206-9615]

Old English Sheepdog – CCDC39 gene, OMIA link: [1540-9615]

Australian Sheepdog – STK36 gene, OMIA link: [2623-9615]

References:

OMIA link: [2173-9615]

Dillard KJ, Hytönen MK, Fischer D, et al. (2018) A splice site variant in INPP5E causes diffuse cystic renal dysplasia and hepatic fibrosis in dogs. PLoS One 13:e0204073.  [pm/30235266]

Contributed by: Stéphanie Dupuis and Kayla Levineand, Class of 2029, Faculté de médecine vétérinaire, Université de Montréal.  (Translation DWS)