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

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 À38A4G) to significantly influence lung function. The same STX1A risk allele was recognized in the European CF Twin and Sibling Study (P ¼ 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.204C4T). 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.

Gene modifiers of cystic fibrosis lung disease: A systematic review

“…92 Studies involving children should use the most robust markers of lung disease severity in this age group, but they have been rarely used in gene modifier studies to date. Only two papers 93,94 used the most sensitive measure of lung function (lung clearance index [LCI]), [95][96][97] and one paper 59 the most sensitive measure of lower respiratory infection (BAL). 98 Computed Tomography (CT) scan results were used more widely, however not in younger age groups where they are very sensitive markers of lung disease severity.…”

Disease-modifying genes and monogenic disorders: experience in cystic fibrosis

“…Additional genes of the CFTR interactome, such as SCNN1B and SCNN1G encoding the β-subunits and γ-subunits of ENaC,78 STX1A ,79 KRT19 , PPP2R4 , PPP2R1A , and SNAP23 ,80 have been found to be involved in the modification of CF lung disease. While the modulating effect of SCNN1B and SCNN1G could not be confirmed,81 the influence of STX1A on lung disease severity was replicated in an independent CF patient cohort and variant rs2228607 was shown to reinforce aberrant splicing of STX1A mRNA, triggering nonsense-mediated mRNA decay and indicating functional relevance of this variant 79. The findings by Gisler et al80 are based upon longitudinal data for six different lung function parameters and are waiting replication; however, to have comparable longitudinal data from an independent CF patient cohort at hand is not simple.…”

“… 76 SLC9A3 reciprocally interacts with CFTR through a regulatory complex including NHERF-2, ezrin, and protein kinase A, and therefore provides plausible genetic evidence of a modulatory effect. 77 Additional genes of the CFTR interactome, such as SCNN1B and SCNN1G encoding the β-subunits and γ-subunits of ENaC, 78 STX1A , 79 KRT19 , PPP2R4 , PPP2R1A , and SNAP23 , 80 have been found to be involved in the modification of CF lung disease. While the modulating effect of SCNN1B and SCNN1G could not be confirmed, 81 the influence of STX1A on lung disease severity was replicated in an independent CF patient cohort and variant rs2228607 was shown to reinforce aberrant splicing of STX1A mRNA, triggering nonsense-mediated mRNA decay and indicating functional relevance of this variant.…”

The ABCC6 transporter: what lessons can be learnt from other ATP-binding cassette transporters?

“…The clinical variability in PXE shows similarities with the variability in cystic fibrosis (CF), the clinical course of which is also difficult to predict using the ABCC7 mutations. Consequently, the quest for modifier genes has started and several modifiers of pulmonary outcome in CF have been described (Blaisdell et al, 2004; Boyle, 2007; Weiler and Drumm, 2012; von Kanel et al, 2013). The search for CF modifiers has lead to several recommendations which are equally valid for ABCC6.…”