Rare bi-allelic loss-of-function variants in the LRRK2 kinase cause interstitial lung disease

Abstract

We report that biallelic LRRK2 loss-of-function (LoF) causes a Mendelian form of interstitial lung disease characterized by alveolar epithelial cell dysfunction and lung fibrosis in two brothers with a homozygous nonsense variant. Integrated clinical, imaging, histopathological, and biomarker analyses showed absent LRRK2 protein, reduced Rab10 phosphorylation, impaired alveolar type 2 cell function, and disrupted surfactant homeostasis. Consistent with a recessive genetic disorder, heterozygous LoF carriers have not been reported to have a lung phenotype. Additional biallelic LRRK2 LoF cases were identified in ILD cohorts, linking LRRK2 LoF to lung disease, in contrast to heterozygous activating missense variants that cause Parkinsons disease (PD).