Intronic ITGA3 Mutation Impacts Splicing Regulation and Causes Interstitial Lung Disease, Nephrotic Syndrome, and Epidermolysis Bullosa Yinghong He,

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Intronic ITGA3 Mutation Impacts Splicing Regulation and Causes Interstitial Lung Disease, Nephrotic Syndrome, and Epidermolysis Bullosa Yinghong He, Meena Balasubramanian, Nigel Humphreys, Catherine Waruiru, Martin Brauner, Juergen Kohlhase, Ruth O'Reilly, Cristina Has Journal of Investigative Dermatology Volume 136, Issue 5, Pages 1056-1059 (May 2016) DOI: 10.1016/j.jid.2015.11.031 Copyright © 2016 The Authors Terms and Conditions

Figure 1 ITGA3 mutation and skin morphological findings. (a) Chromatograms reveal partial sequences of ITGA3. The mutation c.1383-11T>A is indicated by an arrow. The normal ASS is shown by green lines, whereas the new generated aberrant site is marked by red lines. (b) Immunofluorescence staining of the skin of a healthy control and the patient are shown by confocal microscopy. Integrin α3 (high-resolution versions of these slides for use with the Virtual Microscope are available as eSlides: VM02403 and VM02657), integrin α6 (high-resolution version of these slides for use with the Virtual Microscope are available as eSlides: VM02658 and VM02421), laminin α3 (high-resolution versions of these slides for use with the Virtual Microscope are available as eSlides: VM02425 and VM02426), and collagen VII (high-resolution version of these slides for use with the Virtual Microscope are available as eSlides: VM02424 and VM02423) appear in green. The positions of the blisters are depicted by asterisk, and nuclei appear in blue, bars = 100 μm. High resolution versions of these slides are available as V02403, V02404. ASS, acceptor splice site; ITGA3, integrin α3 gene. Journal of Investigative Dermatology 2016 136, 1056-1059DOI: (10.1016/j.jid.2015.11.031) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Consequences of the mutation. (a) qPCR (left) and RT-PCR (right); the arrow shows the lower band, probably transcript 5. (b) Sequencing of transcript 1 demonstrates the insertion of 9 bp from the intron 9 into the reading frame. (c) Representation of transcripts in the skin of the control and patient. Exons: boxes, introns: not at scale, length: in bp, primers: green arrows. (d) Transcripts identified in the patient’s skin by nested PCR using combinations of primers. (e) Nested PCR amplicons, 3F-3R and 5F-3R were analyzed using capillary electrophoresis (Bioanalyzer). Peaks show the most abundant transcripts, 1 and 3. (f) Representation of the consequences of the mutation c.1383-11T>A: generation of a new ASS and ESE. (g) The tertiary structures were modeled and show significant alteration of the conformation of the mutant p.461_462insLCR β-propeller domain. bp, base pairs; ESE, exonic splicing enhancer; qPCR, quantitative real time PCR; RT-PCR, reverse-transcriptase PCR. Journal of Investigative Dermatology 2016 136, 1056-1059DOI: (10.1016/j.jid.2015.11.031) Copyright © 2016 The Authors Terms and Conditions