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.
Highlights
Hepatorenal fibrocystic disorders (HRFCDs) are characterized by developmental portobiliary and renal fibrocystic abnormalities such as polycystic kidneys and congenital hepatic fibrosis
Since INPP5E:c.1572+5G>A resides in a splice site, we investigated the effect on gene expression and possible functional change in the protein sequence (Fig 4A)
The congenital syndrome that we have characterized in the Norwich Terrier is novel both in its pathology and in its genetic background
Summary
Hepatorenal fibrocystic disorders (HRFCDs) are characterized by developmental portobiliary and renal fibrocystic abnormalities such as polycystic kidneys and congenital hepatic fibrosis. HRFCDs belong to a larger group of diseases called ciliopathies that are caused by structural or functional defects in the primary cilium. Ciliopathies are an expanding group of diseases that are clinically and genetically very heterogeneous and can manifest as a congenital developmental syndrome or as progressive single organ dysfunction. INPP5E causes cystic renal dysplasia and hepatic fibrosis in dogs polycystic kidney diseases (ARPKD and ADPKD respectively) are the most common forms of HRFCDs in humans. Kidney and liver lesions variably occur in other syndromic ciliopathies like Joubert, Meckel, Bardet-Biedl and Jeune syndrome [1]
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