Recessive missense LAMP3 variant associated with defect in lamellar body biogenesis and fatal neonatal interstitial lung disease in dogs.

Neonatal interstitial lung diseases due to abnormal surfactant biogenesis are rare in humans and have never been reported as a spontaneous disorder in animals. We describe here a novel lung disorder in Airedale Terrier (AT) dogs with clinical symptoms and pathology similar to the most severe neonatal forms of human surfactant deficiency. Lethal hypoxic respiratory distress and failure occurred within the first days or weeks of life in the affected puppies. Transmission electron microscopy of the affected lungs revealed maturation arrest in the formation of lamellar bodies (LBs) in the alveolar epithelial type II (AECII) cells. The secretory organelles were small and contained fewer lamellae, often in combination with small vesicles surrounded by an occasionally disrupted common limiting membrane. A combined approach of genome-wide association study and whole exome sequencing identified a recessive variant, c.1159G>A, p.(E387K), in LAMP3, a limiting membrane protein of the cytoplasmic surfactant organelles in AECII cells. The substitution resides in the LAMP domain adjacent to a conserved disulfide bond. In summary, this study describes a novel interstitial lung disease in dogs, identifies a new candidate gene for human surfactant dysfunction and brings important insights into the essential role of LAMP3 in the process of the LB formation.

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

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.

Strongyloides stercoralis infection in a Finnish kennel.

BACKGROUND: Intestinal threadworm Strongyloides stercoralis is a parasite of dog, cat and primates that occurs worldwide being most prevalent in tropical and subtropical countries. The adult parasitic worm is about 2 mm long and slender. It possesses both parasitic and free-living lifecycles. The parasitic worms are females. Strongyloides stercoralis infects the host via percutaneous, peroral or transmammary transmission in addition to autoinfection. Clinical disease varies from inapparent to severe enteritis and pneumonia. The diagnosis is based on demonstration of larvae in fresh faeces, which is best made by Baermann technique. CASE PRESENTATION: Strongyloides stercoralis infection was diagnosed in autopsy in a 10-week-old puppy born and raised in a Finnish kennel. Prior to its sudden death, the puppy had suffered from gastrointestinal disturbance for three weeks. Subsequent sampling of the dogs in the kennel revealed that three adult dogs in the kennel were also infected. CONCLUSION: The present case shows that S. stercoralis can complete its life cycle and cause disease in dogs also in Northern Europe. Infection can be maintained also in a temperate climate and may become a chronic problem in a kennel environment. Infection may be underdiagnosed as Baermann technique is not routinely performed in small animal practice.