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Marfan Syndrome Variability: Investigation of the Roles of Sarcolipin and Calcium as Potential Transregulator of FBN1 Expression


Marfan Syndrome Variability: Investigation of the Roles of Sarcolipin and Calcium as Potential Transregulator of FBN1 Expression

Louise Benarroch et al. Genes (Basel).


Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that displays a great clinical variability. Previous work in our laboratory showed that fibrillin-1 (FBN1) messenger RNA (mRNA) expression is a surrogate endpoint for MFS severity. Therefore, an expression quantitative trait loci (eQTL) analysis was performed to identify trans-acting regulators of FBN1 expression, and a significant signal reached genome-wide significant threshold on chromosome 11. This signal delineated a region comprising one expressed gene, SLN (encoding sarcolipin), and a single pseudogene, SNX7-ps1 (CTD-2651C21.3). We first investigated the region and then looked for association between the genes in the region and FBN1 expression. For the first time, we showed that the SLN gene is weakly expressed in skin fibroblasts. There is no direct correlation between SLN and FBN1 gene expression. We showed that calcium influx modulates FBN1 gene expression. Finally, SLN gene expression is highly correlated to that of the neighboring SNX7-ps1. We were able to confirm the impact of calcium influx on FBN1 gene expression but we could not conclude regarding the role of sarcolipin and/or the eQTL locus in this regulation.

Keywords: Marfan syndrome; calcium; fibrillin-1; genetic modifiers; sarcolipin; variability.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; and in the decision to publish the results.


Figure 1
Figure 1
Linkage disequilibrium (LD) block for (fibrillin-1) FBN1 expression transregulator region at 11q22.3: (a) Cytogenetic localization and sequence coordinates of lead single nucleotide polymorphisms (SNPs) in red; (b) Regional LD map. Data were extracted from HapMap using Haploview. Linkage disequilibrium was measured as r2 values which range from 0 (no correlation) to 1 (complete correlation). SNPs in complete LD (r2 = 1) with SNPs identified by eQTL analysis are highlighted in yellow.
Figure 2
Figure 2
Correlation of expression levels between FBN1 SLN and SNX7-ps1 gene. (a) Gene expression levels were assessed using digital droplet PCR (ddPCR). Positive correlation of expression was observed between the nearest gene of the lead SNP, SLN and SNX7-ps1 (r2 = 0.86, p-value < 0.0001). (b) Correlation plot between FBN1 and SLN expression. No correlation was found (r2 = 0.0009, p-value = 0.56). (c) Correlation plot between FBN1 and SNX7-ps1 expression. No correlation was found (r2 < 0.0001, p-value = 0.56).
Figure 3
Figure 3
Effect of A23187 on gene expression. Patients’ skin fibroblasts were incubated with DMSO (untreated), 1 µM or 10 µM of A23187 for 4 h, 24 h, and 48 h. (a) FOS gene expression. (b) FBN1 gene expression after treatment with A23187 (Control vs. 4 h: p-value = 0.0082; Control vs. 24 h: p-value < 0.0001; Control vs. 48 h: p-value < 0.0001). (c) FBN1 gene expression according to rs11212346 genotype (Control vs. 4 h: p-value = 0.0906; Control vs. 24 h: p-value = 0.0075; Control vs. 48 h: p-value < 0.0001). Genotype: [CC] (n= number of subject); [CT] (n); [TT] (n). [NS] p-value > 0.05; ** p-value < 0.01; *** p-value < 0.001; **** p-value < 0.0001.

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