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

TitleLack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.
Publication TypeJournal Article
Year of Publication2019
AuthorsBustamante-Marin, XM, Yin, W-N, 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
JournalAm J Hum Genet
Volume104
Issue2
Pagination229-245
Date Published2019 Feb 07
ISSN1537-6605
Abstract

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.Val296Glyfs13), 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.

DOI10.1016/j.ajhg.2018.12.009
Alternate JournalAm. J. Hum. Genet.
PubMed ID30665704
PubMed Central IDPMC6372263
Grant ListHHSN268201100037C / HL / NHLBI NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States
UC2 HL102926 / HL / NHLBI NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
P30 CA016086 / CA / NCI NIH HHS / United States
U54 HL096458 / HL / NHLBI NIH HHS / United States
R01 HL117836 / HL / NHLBI NIH HHS / United States
R01 HL071798 / HL / NHLBI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
UL1 TR000083 / TR / NCATS NIH HHS / United States
R01 GM089970 / GM / NIGMS NIH HHS / United States
P30 DK065988 / DK / NIDDK NIH HHS / United States