Rare bi-allelic loss-of-function variants in the LRRK2 kinase cause interstitial lung disease
Sammler, E. M.; Kalacyi, T.; Wikenheiser-Brokamp, K. A.; Gomes, S.; Rawat, E. S.; Peljto, A.; Cheung, A.; Citak, S.; Vayvada, M.; Montero-Fernandez, M. A.; Mogulkoc, N.; Okumus, N. G.; Suer, I.; Kitzmiller, J.; Na, C.-L.; Li, X.; Bell, S.; Cook, K. C. S.; Abu-Remaileh, M.; Schwartz, D. A.; Uyguner, Z. O.; Whitsett, J. A.; Alessi, D. R.; Zimprich, A.; Zacharias, W. J.
Show abstract
We report that biallelic loss-of-function of LRRK2 causes a Mendelian form of interstitial lung disease characterized by lung fibrosis and alveolar epithelial cell dysfunction 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 bi-allelic LRRK2 LoF cases were identified in ILD cohorts, linking LRRK2 to lung disease, in contrast to heterozygous activating missense variants that cause Parkinsons disease.
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