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Am J Hum Genet 2019 Feb 07;1042:229-245. doi: 10.1016/j.ajhg.2018.12.009.
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Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.

Bustamante-Marin XM , Yin WN , Sears PR , Werner ME , Brotslaw EJ , Mitchell BJ , Jania CM , Zeman KL , Rogers TD , Herring LE , Refabért L , Thomas L , Amselem S , Escudier E , Legendre M , Grubb BR , Knowles MR , Zariwala MA , Ostrowski LE .

Primary ciliary dyskinesia (PCD) is a genetic disorder in which impaired ciliary function leads to chronic airway disease. Exome sequencing of a PCD subject identified an apparent homozygous frameshift variant, c.887_890delTAAG (p.Val296Glyfs∗13), in exon 5; this frameshift introduces a stop codon in amino acid 308 of the growth arrest-specific protein 2-like 2 (GAS2L2). Further genetic screening of unrelated PCD subjects identified a second proband with a compound heterozygous variant carrying the identical frameshift variant and a large deletion (c.867_∗343+1207del; p.?) starting in exon 5. Both individuals had clinical features of PCD but normal ciliary axoneme structure. In this research, using human nasal cells, mouse models, and X.laevis embryos, we show that GAS2L2 is abundant at the apical surface of ciliated cells, where it localizes with basal bodies, basal feet, rootlets, and actin filaments. Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8 Hz versus control = 15.8 Hz) ciliary-beat pattern. These results were recapitulated in Gas2l2-/- mouse tracheal epithelial cell (mTEC) cultures and in X. laevis embryos treated with Gas2l2 morpholinos. In mice, the absence of Gas2l2 caused neonatal death, and the conditional deletion of Gas2l2 impaired mucociliary clearance (MCC) and led to mucus accumulation. These results show that a pathogenic variant in GAS2L2 causes a genetic defect in ciliary orientation and impairs MCC and results in PCD.

PubMed ID: 30665704
PMC ID: PMC6372263
Article link: Am J Hum Genet
Grant support: [+]

Species referenced: Xenopus
Genes referenced: cdkn1a cntrl cox7a2l crocc efnb3 gas2 hbe1 kidins220 lamtor2 mcc muc5b pcbd1 rho she tbp tgfbi

Disease Ontology terms: primary ciliary dyskinesia

Article Images: [+] show captions
References [+] :
Au, GAS2L1 Is a Centriole-Associated Protein Required for Centrosome Dynamics and Disjunction. 2017, Pubmed