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

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Dillard , K J , Ochs , M , Niskanen , J E , Arumilli , M , Donner , J , Kyöstilä , K , Hytönen , M K , Anttila , M & Lohi , H 2020 , ' Recessive missense LAMP3 variant associated with defect in lamellar body biogenesis and fatal neonatal interstitial lung disease in dogs ' , PLoS Genetics , vol. 16 , no. 3 , 1008651 . https://doi.org/10.1371/journal.pgen.1008651

Title: Recessive missense LAMP3 variant associated with defect in lamellar body biogenesis and fatal neonatal interstitial lung disease in dogs
Author: Dillard, Kati J.; Ochs, Matthias; Niskanen, Julia E.; Arumilli, Meharji; Donner, Jonas; Kyöstilä, Kaisa; Hytönen, Marjo K.; Anttila, Marjukka; Lohi, Hannes
Contributor: University of Helsinki, Veterinary Biosciences
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Genoscoper Laboratories Ltd
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Department of Medical and Clinical Genetics
University of Helsinki, Helsinki One Health (HOH)
Date: 2020-03-09
Language: eng
Number of pages: 19
Belongs to series: PLoS Genetics
ISSN: 1553-7390
URI: http://hdl.handle.net/10138/314666
Abstract: 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. Author summary We have characterized a lethal lung disease in neonatal Airedale Terrier dogs. The pathological features of the disease resemble those of the surfactant dysfunction in newborn babies. Surfactant is essential for lung function and we observed a maturation defect in the surfactant producing organelles of the lung epithelial type II cells. Genetic analyses revealed a recessive variant in the lysosome associated membrane LAMP3 gene. LAMP3 is a structural, limiting membrane protein of the surfactant organelles. This study provides an excellent candidate gene for human surfactant disorders as well as new insights into LAMP3 biology and pathophysiology while the affected breed will benefit from genetic testing to eradicate this severe disease.
Subject: 3Q26.33-3Q27.2 MICRODELETION
ABCA3
II PNEUMOCYTES
LIPID TRANSPORTER
MEMBRANE-PROTEIN
PULMONARY SURFACTANT
RESPIRATORY-DISTRESS
SURFACTANT PROTEIN-B
TYPE-2 ALVEOLAR CELLS
ULTRASTRUCTURE
413 Veterinary science
1184 Genetics, developmental biology, physiology
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