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

Biallelic LRRK2 LOF variants → absent LRRK2 protein → impaired Rab10 phosphorylation → alveolar type 2 cell dysfunction → disrupted surfactant homeostasis → pulmonary fibrosis

Biallelic loss-of-function variants in LRRK2 cause a Mendelian form of interstitial lung disease in two brothers with a homozygous nonsense variant. Clinical, histopathological, and biomarker analyses show absent LRRK2 protein, reduced Rab10 phosphorylation, impaired alveolar type 2 cell function, and disrupted surfactant homeostasis. Additional biallelic cases were identified in ILD cohorts, in striking contrast with heterozygous gain-of-function LRRK2 variants causing Parkinson's disease.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The LRRK2 duality is fascinating: heterozygous gain-of-function → Parkinson's disease; biallelic loss-of-function → pulmonary fibrosis. This allele-specific contrast perfectly illustrates the reverse genetics paradigm and raises important questions about the potential effects of LRRK2 inhibitors (in development for Parkinson's) in recessive variant carriers. Preprint to follow for journal confirmation.

Clinical impact: 2/3 · Evidence strength: 2/3 · Novelty: 2/2 · Sample size: 0/1 · Journal quality: 0/1 · Preprint: -1 → Total: 5/10