TY - JOUR T1 - The discovery of novel mechanisms for lymphangioleiomyomatosis pathogenesis through GWAS: a rarity in rare respiratory disorders JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.00863-2019 VL - 53 IS - 6 SP - 1900863 AU - Arnold S. Kristof AU - Victor E. Ortega Y1 - 2019/06/01 UR - http://erj.ersjournals.com/content/53/6/1900863.abstract N2 - Lymphangioleiomyomatosis (LAM) is a rare respiratory disorder primarily of women that can occur sporadically (S-LAM), or as a manifestation of tuberous sclerosis complex (TSC) [1]. TSC is a syndrome of neurodevelopmental disorders and tumours in multiple organs, caused by heterozygous germline variants in the TSC1 or TSC2 genes, which can be inherited in autosomal dominant fashion or which can occur de novo [2, 3]. The TSC1 and TSC2 gene products, hamartin (TSC1) and tuberin (TSC2), constitute a heterodimeric suppressor of the kinase “mechanistic target of rapamycin complex 1” (mTORC1). In both TSC- and S-LAM, tumours arise via somatic loss of the functional “wild-type” allele (i.e. loss of heterozygosity) at the TSC1 or TSC2 locus, resulting in excessive mTOR activity, uninhibited cell growth, and unchecked neoplastic behaviour. In individuals with LAM, microscopic pulmonary interstitial tumours consisting of TSC2-deficient “LAM cells” progressively destroy the lung, culminating in death or lung transplantation.This is the largest genome-wide association study of risk for sporadic LAM, a rare genetic disorder, from an international effort which identified novel variants for LAM pathogenesis in a plausible gene, independent of variation in TSC1 and TSC2 http://bit.ly/2X0SeZ1 ER -