A splice site variant in INPP5E causes diffuse cystic renal dysplasia and hepatic fibrosis in dogs

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Dillard , K J , Hytönen , M K , Fischer , D , Tanhuanpää , K , Lehti , M S , Vainio-Siukola , K , Sironen , A & Anttila , M 2018 , ' A splice site variant in INPP5E causes diffuse cystic renal dysplasia and hepatic fibrosis in dogs ' , PLoS One , vol. 13 , no. 9 , 0204073 . https://doi.org/10.1371/journal.pone.0204073

Title: A splice site variant in INPP5E causes diffuse cystic renal dysplasia and hepatic fibrosis in dogs
Author: Dillard, Kati J.; Hytönen, Marjo K.; Fischer, Daniel; Tanhuanpää, Kimmo; Lehti, Mari S.; Vainio-Siukola, Katri; Sironen, Anu; Anttila, Marjukka
Contributor organization: Research Programs Unit
Doctoral Programme in Clinical Veterinary Medicine
Doctoral Programme in Integrative Life Science
Research Programme for Molecular Neurology
Veterinary Biosciences
Veterinary Genetics
Hannes Tapani Lohi / Principal Investigator
Research Programme of Molecular Medicine
Faculty of Veterinary Medicine
Institute of Biotechnology
Date: 2018-09-20
Language: eng
Number of pages: 18
Belongs to series: PLoS One
ISSN: 1932-6203
DOI: https://doi.org/10.1371/journal.pone.0204073
URI: http://hdl.handle.net/10138/248740
Abstract: 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.
413 Veterinary science
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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