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. 2019 Feb 11;10(2):128.
doi: 10.3390/genes10020128.

Reference Expression Profile of Three FBN1 Transcript Isoforms and Their Association with Clinical Variability in Marfan Syndrome

Louise Benarroch  1 , Mélodie Aubart  2   3 , Marie-Sylvie Gross  4 , Pauline Arnaud  5   6 , Nadine Hanna  7 , Guillaume Jondeau  8   9   10 , Catherine Boileau  11   12   13
Affiliations

Reference Expression Profile of Three FBN1 Transcript Isoforms and Their Association with Clinical Variability in Marfan Syndrome

Louise Benarroch et al. Genes (Basel). .

Abstract

Marfan syndrome (MFS) is a rare connective tissue disorder mainly due to mutations in the FBN1 gene. Great phenotypic variability is notable for age of onset, the presence and absence, and the number and the severity of the symptoms. Our team showed that FBN1 gene expression level was a good surrogate endpoint for severity of some MFS clinical features. Eight alternative transcripts are referenced for the FBN1 gene. We hypothesized that MFS clinical variability could be related to specific FBN1 isoforms. Isoform expression profiles were investigated in skin and adventitial fibroblasts from controls and MFS patients. The results of the study showed that, in skin and adventitial fibroblasts, only three isoforms were found: FBN1_001, FBN1_004, and FBN1_009. The main isoform was FBN1_001 and it was significantly reduced in skin and adventitial fibroblasts of MFS patients. The expressions of FBN1_004 and FBN1_009 isoforms were similar between controls and MFS patients. However, the expression of the three isoforms was correlated only in patients. Furthermore, their expression levels were associated with the presence of ectopia lentis in MFS patients. Therefore, our results highlight that the two minor alternatively spliced FBN1 isoforms play a possible role in the pathogenesis of the disease.

Keywords: Marfan syndrome; alternative splicing; clinical variability; fibrilline-1; isoforms.

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Conflict of interest statement

The authors declare no conflicts 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.

Figures

Figure 1
Figure 1
Description of expressed FBN1 isoforms. (a) In silico analysis of FBN1 isoforms expressed in skin fibroblasts from controls and Marfan syndrome (MFS) patients. Colored boxes represent exons, and coding (boxes with black borders) and non-coding (boxes with gray borders) regions. Exons are numbered in accordance with the referenced sequence (FBN1_001 isoform) above the boxes. Bold red asterisks indicate exons specific to each isoform. The purple lines indicate the localization of each set of primers used to quantify the expression of each isoform. MFS patients were divided into three groups depending on where the mutation was located: group I (mutations in exons 1 to 37, included), group II (exons 38 to 63, included), and group III (exons 64 to 66, included). (b) FBN1 isoform expressions in skin and adventitial fibroblasts. Quantification using real-time quantitative PCR (RT-qPCR) was performed in skin fibroblasts from 15 controls and 42 MFS patients and in adventitial fibroblasts from five patients with thoracic aortic aneurysm (TAA). (c) Correlation of expression between skin and adventitial fibroblasts. Comparison of FBN1 messenger RNA (mRNA) level for five TAA patients.
Figure 2
Figure 2
FBN1 isoform expressions and FBN1 mutation locations. (a) FBN1 isoform expression levels in controls and MFS patients. A significant decrease in expression was found for MFS patients regarding FBN1 total expression (p < 0.0001) and FBN1_001 expression (p < 0.0001). No significant difference was found for the other two isoforms (FBN1_004 and FBN1_009). (b) Isoform expression levels in group I. A significant decrease in expression was found for FBN1 total expression (p < 0.0001) and FBN1_001 expression (p < 0.0001). No difference was observed for FBN1_004 and FBN1_009. (c) Isoform expression levels in group II. A significant decrease in expression was found for FBN1 total expression (p < 0.0001), FBN1_001 expression (p < 0.0001), and FBN1_004 expression (p = 0.015). No difference was observed for FBN1_009. (d) Isoform expression levels in group III. A significant decrease in expression was found for FBN1 total expression (p < 0.0001) and FBN1_001 expression (p < 0.0001). No difference was observed for FBN1_004 and FBN1_009. NS: p > 0.05; *: p < 0.05; ****: p < 0.0001.
Figure 3
Figure 3
Correlation of expression levels between FBN1 isoforms. (a) Expression levels were assessed in controls. A positive correlation was found between FBN1_001 and FBN1_009 expressions. No correlations were found between FBN1_004 expression and that of the other two isoforms (FBN1_001 and FBN1_009). (b) Expression levels were assessed in MFS patients. A positive correlation was found between the three isoforms.
Figure 4
Figure 4
FBN1 mRNA expression levels in MFS patients with or without ectopia lentis. (a) Total FBN1 expression; (b) FBN1_001 expression; (c) FBN1_004 expression; (d) FBN1_009 expression. Diamond plots display the means of each group. The line across each diamond represents the group mean, and the vertical span of each diamond represents the 95% confidence interval for each group.
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References

    1. Collod-Béroud G., Béroud C., Adès L., Black C., Boxer M., Brock D.J., Godfrey M., Hayward C., Karttunen L., Milewicz D., et al. Marfan Database (second edition): software and database for the analysis of mutations in the human FBN1 gene. Nucleic Acids Res. 1997;25:147–150. doi: 10.1093/nar/25.1.147. - DOI - PMC - PubMed
    1. Loeys B.L., Dietz H.C., Braverman A.C., Callewaert B.L., De Backer J., Devereux R.B., Hilhorst-Hofstee Y., Jondeau G., Faivre L., Milewicz D.M., et al. The revised Ghent nosology for the Marfan syndrome. J. Med. Genet. 2010;47:476–485. doi: 10.1136/jmg.2009.072785. - DOI - PubMed
    1. Baudhuin L.M., Kotzer K.E., Lagerstedt S.A. Increased frequency of FBN1 truncating and splicing variants in Marfan syndrome patients with aortic events. Genet. Med. 2015;17:177–187. doi: 10.1038/gim.2014.91. - DOI - PubMed
    1. Becerra-Muñoz V.M., Gómez-Doblas J.J., Porras-Martín C., Such-Martínez M., Crespo-Leiro M.G., Barriales-Villa R., de Teresa-Galván E., Jiménez-Navarro M., Cabrera-Bueno F. The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. Orphanet J. Rare Dis. 2018;13:16. doi: 10.1186/s13023-017-0754-6. - DOI - PMC - PubMed
    1. Faivre L., Collod-Beroud G., Loeys B.L., Child A., Binquet C., Gautier E., Callewaert B., Arbustini E., Mayer K., Arslan-Kirchner M., et al. Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: An international study. Am. J. Hum. Genet. 2007;81:454–466. doi: 10.1086/520125. - DOI - PMC - PubMed

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