Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance

Ximena M. Bustamante-Marin, Wei Ning Yin, Patrick R. Sears, Michael E. Werner, Eva J. Brotslaw, Brian J. Mitchell, Corey M. Jania, Kirby L. Zeman, Troy D. Rogers, Laura E. Herring, Luc Refabért, Lucie Thomas, Serge Amselem, Estelle Escudier, Marie Legendre, Barbara R. Grubb, Michael R. Knowles, Maimoona A. Zariwala, Lawrence E. Ostrowski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)229-245
Number of pages17
JournalAmerican journal of human genetics
Issue number2
StatePublished - Feb 7 2019


  • GAS2L2
  • MCC
  • PCD
  • ciliary orientation
  • mucociliary clearance
  • primary ciliary dyskinesia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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