A1 Refereed original research article in a scientific journal
A splice site variant in INPP5E causes diffuse cystic renal dysplasia and hepatic fibrosis in dogs
Authors: Dillard KJ, Hytonen MK, Fischer D, Tanhuanpaa K, Lehti MS, Vainio-Siukola K, Sironen A, Anttila M
Publisher: PUBLIC LIBRARY SCIENCE
Publication year: 2018
Journal: PLoS ONE
Journal name in source: PLOS ONE
Journal acronym: PLOS ONE
Article number: ARTN e0204073
Volume: 13
Issue: 9
Number of pages: 18
ISSN: 1932-6203
DOI: https://doi.org/10.1371/journal.pone.0204073
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/35995738
Ciliopathies presenting as inherited hepatorenal fibrocystic disorders are rare in humans and in dogs. We describe here a novel lethal ciliopathy in Norwich Terrier puppies that was diagnosed at necropsy and characterized as diffuse cystic renal disease and hepatic fibrosis. The histopathological findings were typical for cystic renal dysplasia in which the cysts were located in the straight portion of the proximal tubule, and thin descending and ascending limbs of Henle's loop. The pedigree of the affected puppies was suggestive of an autosomal recessive inheritance and therefore, whole exome sequencing and homozygosity mapping were used for identification of the causative variant. The analyses revealed a case-specific homozygous splice donor site variant in a cilia related gene, INPP5E: c.1572+5G>A. Association of the variant with the defect was validated in a large cohort of Norwich Terriers with 3 cases and 480 controls, the carrier frequency being 6%. We observed that the identified variant introduces a novel splice site in INPP5E causing a frameshift and formation of a premature stop codon. In conclusion, our results suggest that the INPP5E: c.1572+5G>A variant is causal for the ciliopathy in Norwich Terriers. Therefore, genetic testing can be carried out in the future for the eradication of the disease from the breed.
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