Genotype frequencies of the five SNPs for the <i>FXN</i> 3′-UTR in cases, cases from the replication study (RS-cases), and controls.

<p>Genotype frequencies of the five SNPs for the <i>FXN</i> 3′-UTR in cases, cases from the replication study (RS-cases), and controls.</p

Frequencies of the haplotypes comprising the five SNPs of the <i>FXN</i> 3′-UTR.

<p>Frequencies of the haplotypes comprising the five SNPs of the <i>FXN</i> 3′-UTR.</p

Distribution of the most common haplotypes.

<p>Genotype frequencies of haplotypes in cases, controls and the replication study cases (RS-cases) are plotted as pie charts for the most common haplotypes of the <i>FXN</i> 3′-UTR (TGCTT, CATCG, CATCT). Haplotype TATTT was uniquely found among RS-cases.</p

Computational analysis of miRNA targeting on <i>FXN</i> 3′-UTR.

<p>Computational analysis of miRNA targeting on <i>FXN</i> 3′-UTR.</p

Schematized representation of the genomic structure of the <i>FXN</i> gene.

<p> The pathogenic expansion of the GAA repeat within intron 1 is indicated by a triangle, exons by grey boxes, respectively dark when translated and light when untranslated. Short genetic variations are indicated as black bars. The <i>FXN</i> 3′-UTR region, which was sequenced is highlighted by a square bracket.</p

Functional assessment of FRDA-3′-UTR versus WT-3′-UTR.

<p> U2OS (black bars) and HEK-293 (grey bars) cells were transfected with luciferase reporter gene system, respectively 150 ng of empty plasmid or plasmid WT-3′-UTR or plasmid FRDA-3′-UTR. Histograms show the <i>Renilla</i> luciferase activity (normalized to firefly luciferase and to the mock transfected cells) following transfection of each plasmid into both cell lines. All results represent mean ± SEM of three independent experiments, each in triplicate. *<i>P</i><0.05, Student-t test.</p

Genetic association of ITR3 and SNPs of the <i>FXN</i> 3′-UTR with FRDA haplotype in cases versus controls.

<p>Genetic association of ITR3 and SNPs of the <i>FXN</i> 3′-UTR with FRDA haplotype in cases versus controls.</p

Lung, heart, liver and kidney weight relative to body weight, in IGF-1R^+/+ and IGF-1R^−/− embryos.

<p>Values are mean ± SEM. * <i>P</i><0.05; ** <i>P</i><0.01; *** <i>P</i><0.001 compared with IGF-1R^+/+ mice. Student’s <i>t</i>-test.</p>a<p>n = 5; BW, body weight; ND, not determined.</p

Lung development in late gestation IGF-1R^−/− mice.

<p><b>A–L</b>, Lungs prepared from IGF-1R^+/+ and IGF-1R^−/− embryos at developmental stages E14.5, E17.5 and E19.5. <b>A–F</b>, Ventral view of whole lungs. <b>G–L</b>, Rim of lung lobe. Abbreviations: AL, apical lobe; AzL, azygous lobe; CL, cardiac lobe; DL, diaphragmatic lobes; LL, left lobe. <b>M–X</b>, Lung histology of IGF-1R^+/+ versus IGF-1R^−/− embryos. H&E stained lung sections at developmental stages E14.5 (<b>M</b>–<b>P</b>), E17.5 (<b>Q</b>–<b>T</b>) and E19.5 (<b>U</b>–<b>X</b>), showing that saccular walls are thicker and acinar buds smaller in IGF-1R^−/− embryos as compared with controls of the same stage. Note that histomorphological appearance is similar when comparing E19.5 IGF-1R^−/− (<b>V</b>, <b>X</b>) with two days younger E17.5 IGF-1R^+/+ lungs (<b>Q</b>, <b>S</b>).</p

Development of diaphragm and chest in the absence of IGF-1R.

<p><b>A</b>, Hematoxylin-eosin stained transversal section of thoracic wall and diaphragm in control (left) and IGF-1R^−/− embryos (right) at E17.5. Bar graphs compare <b>B</b>, diaphragm thickness, <b>C</b>, rib diameter, and <b>D</b>, diaphragm-to-rib ratio (mean ± SEM) in IGF-1R^+/+ embryos (n = 4) and IGF-1R^−/− embryos (n = 4). R, Rib; D, diaphragm. Wilcoxon Mann-Whitney U test.</p