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

PLoS Genetics
Kati J DillardHannes Lohi

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 surfacta...Continue Reading

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Citations

May 30, 2020·Translational Psychiatry·R SarviahoH Lohi
Jun 24, 2021·PLoS Genetics·Lars P LundingMarkus Damme

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Datasets Mentioned

BETA
PRJNA515838

Methods Mentioned

BETA
transmission electron microscopy
genotyping
exome sequencing
glycosylation
bronchoalveolar lavage
light microscopy
PCR
chip

Software Mentioned

Burrows
Mobile Element Locator Tool ( MELT )
HaplotypeCaller
PredictSNP
Picard
DELLY
GeneCodes
Genotype Query Tools
GenoPro
- Aligner ( BWA )

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