Biallelic LAMP3 Variants in Five Families with Interstitial Lung Disease: Evidence of a Disease-Gene Association

Abstract

Purpose: Genetic causes of surfactant dysfunction are associated with childhood interstitial lung disease (chILD). Lysosome-associated membrane glycoprotein 3 (LAMP3) is highly expressed within lamellar bodies of alveolar epithelial type II cells, and variants in LAMP3 have recently been suggested as a novel cause of chILD. This study describes the phenotypes of participants with biallelic variants in LAMP3 and presents functional studies evaluating the role of specific LAMP3 variants.

Methods: Phenotypic data was collected through chart review and clinical evaluation. In vitro effects of LAMP3 variants were evaluated through immunohistochemistry, WB, and flow cytometry.

Results: Thirteen participants were identified with biallelic variants in LAMP3. They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood. All symptomatic participants demonstrated ground glass opacities early in life and lung fibrosis later in life. For one participant, BAL analysis showed abnormal surfactant protein composition and lung biopsy revealed irregular LB. In vitro studies in lung epithelial cells with induced expression of specific LAMP3 variants demonstrated reduced protein expression and abnormal glycosylation.

Conclusions: Biallelic LAMP3 variants are associated with an interstitial lung disease phenotype with variable expressivity. Evaluation for LAMP3 variants should be considered in individuals with unexplained interstitial lung disease.

Keywords: LAMP3; interstitial lung disease; surfactant dysfunction.