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

Autoři: Kati J. Dillard aff001;  Matthias Ochs aff005;  Julia E. Niskanen aff001;  Meharji Arumilli aff001;  Jonas Donner aff008;  Kaisa Kyöstilä aff001;  Marjo K. Hytönen aff001;  Marjukka Anttila aff004;  Hannes Lohi aff001
Působiště autorů: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland aff001;  Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland aff002;  Folkhälsan Research Center, Helsinki, Finland aff003;  Veterinary Bacteriology and Pathology Research Unit, Finnish Food Authority, Helsinki, Finland aff004;  Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany aff005;  Institute of Functional Anatomy, Charité - Universitaetsmedizin Berlin, Berlin, Germany aff006;  German Center for Lung Research (DZL), Berlin, Germany aff007;  Genoscoper Laboratories Ltd (Wisdom Health), Helsinki, Finland aff008
Vyšlo v časopise: Recessive missense LAMP3 variant associated with defect in lamellar body biogenesis and fatal neonatal interstitial lung disease in dogs. PLoS Genet 16(3): e1008651. doi:10.1371/journal.pgen.1008651
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008651


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.

Klíčová slova:

Cellular structures and organelles – Dogs – Genome-wide association studies – Interstitial lung diseases – Lungs – Mammalian genomics – Pets and companion animals – Surfactants


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