Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A

von Kanel, Thomas; Stanke, Frauke; Weber, Melanie; Schaller, Andre; Racine, Julien; Kraemer, Richard; Chanson, Marc; Tümmler, Burkhard; Gallati, Sabina (2013). Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A. European journal of human genetics, 21(12), pp. 1462-1466. Houndmills, UK: Nature Publishing Group

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Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR). Disease severity in CF varies greatly, and sibling studies strongly indicate that genes other than CFTR modify disease outcome. Syntaxin 1A (STX1A) has been reported as a negative regulator of CFTR and other ion channels. We hypothesized that STX1A variants act as a CF modifier by influencing the remaining function of mutated CFTR. We identified STX1A variants by genomic resequencing patients from the Bernese CF Patient Data Registry and applied linear mixed model analysis to establish genotype-phenotype correlations, revealing STX1A rs4363087 (c.467-38A>G) to significantly influence lung function. The same STX1A risk allele was recognized in the European CF Twin and Sibling Study (P=0.0027), demonstrating that the genotype-phenotype association of STX1A to CF disease severity is robust enough to allow replication in two independent CF populations. rs4363087 is in linkage disequilibrium to the exonic variant rs2228607 (c.204C>T). Considering that neither rs4363087 nor rs2228607 changes the amino-acid sequence of STX1A, we investigated their effects on mRNA level. We show that rs2228607 reinforces aberrant splicing of STX1A mRNA, leading to nonsense-mediated mRNA decay. In conclusion, we demonstrate the clinical relevance of STX1A variants in CF, and evidence the functional relevance of STX1A variant rs2228607 at molecular level. Our findings show that genes interacting with CFTR can modify CF disease progression.European Journal of Human Genetics advance online publication, 10 April 2013; doi:10.1038/ejhg.2013.57.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
UniBE Contributor:	Schaller, André, Gallati, Sabina
ISSN:	1018-4813
Publisher:	Nature Publishing Group
Language:	English
Submitter:	Anette van Dorland
Date Deposited:	04 Oct 2013 14:41
Last Modified:	05 Dec 2022 14:12
PubMed ID:	23572023
URI:	https://boris.unibe.ch/id/eprint/16530 (FactScience: 224183)