UNIGE document Scientific Article
previous document  unige:29332  next document
add to browser collection

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
Tümmler, Burkhard
show hidden authors show all authors [1 - 9]
Published in European Journal of Human Genetics. 2013, vol. 21, no. 12, p. 1462-1466
Abstract 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.
Keywords cystic fibrosisCF modifierCFTR interactorsyntaxin 1A (STX1A)variantsplicing
PMID: 23572023
Full text
Article (Published version) (383 Kb) - document accessible for UNIGE members only Limited access to UNIGE
Research group Mucoviscidose et jonctions GAP (229)
(ISO format)
VON KANEL, Thomas et al. Clinical and molecular characterization of the potential CF disease modifier syntaxin 1A. In: European Journal of Human Genetics, 2013, vol. 21, n° 12, p. 1462-1466. https://archive-ouverte.unige.ch/unige:29332

169 hits

1 download


Deposited on : 2013-08-15

Export document
Format :
Citation style :