Mutation of IGFBP7 Causes Upregulation of BRAF/MEK/ERK Pathway and Familial Retinal Arterial Macroaneurysms Leen Abu-Safieh, Emad B. Abboud, Hisham Alkuraya,

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Mutation of IGFBP7 Causes Upregulation of BRAF/MEK/ERK Pathway and Familial Retinal Arterial Macroaneurysms Leen Abu-Safieh, Emad B. Abboud, Hisham Alkuraya, Hanan Shamseldin, Shamsa Al-Enzi, Lama Al-Abdi, Mais Hashem, Dilek Colak, Abdullah Jarallah, Hala Ahmad, Steve Bobis, Georges Nemer, Fadi Bitar, Fowzan S. Alkuraya The American Journal of Human Genetics Volume 89, Issue 2, Pages 313-319 (August 2011) DOI: 10.1016/j.ajhg.2011.07.010 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 FRAM Is an Autosomal-Recessive Syndrome Defined by Retinal and Cardiac Phenotypes (A) Pedigrees of eight Saudi families with FRAM. Note the positive consanguinity in all families and the pseudodominant inheritance in family 004. (B) Representative fundus photo showing marked beading of the retinal artery on the optic nerve and along the major trunks. Many macroaneursyms are seen, either that are actively leaking with hard yellow exudate or that are cicatricial. (C) A short-axis view of the echocardiography, showing color turbulence with a Doppler pulse wave, giving a gradient of 20 mmHg at the supravalvular level of the pulmonary outflow tract. (D) Clinical photograph of a patient with FRAM; note the lack of facial dysmorphism. The American Journal of Human Genetics 2011 89, 313-319DOI: (10.1016/j.ajhg.2011.07.010) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 FRAM Is Caused by a Founder Splicing Mutation in IGFBP7 (A) Linkage analysis showing a very high LOD score of 11.4 on chromosome 4 on the first five families combined. Dotted lines emerging from the highest peak demarcate the critical linkage interval, which is further narrowed by the heterozygosity observed for flanking markers rs76451666 and D4S398, which only encompasses six genes, including IGFBP7 (shown in red with sequence chromatogram indicating the site of the G>A transition by a red asterisk). The common founder haplotype is flanked by D4S1592 and rs12501656. (B) RT-PCR and 3′RACE, respectively, confirm the skipping of exon 5 and the lack of polyadenylation of the resulting aberrant transcript. (C) Immunoblot analysis shows more intense (130%) IGFBP7 in patient lymphoblasts (family F005 II-1, II-2 and II-4, from left to right) than in the control. The American Journal of Human Genetics 2011 89, 313-319DOI: (10.1016/j.ajhg.2011.07.010) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 Igfbp7 Is Expressed in the Retinal Vasculature (A) WISH on E12 mouse embryos showing expression domains in the eye (lens and surrounding retina); a sense probe is shown as a negative control. (B) A flat-mount retina is used for immunohistochemistry with Igfbp7 antibody and isolectin-IB4 stain (latter is a marker for blood vessels). Note the positive staining in the superficial scans (1–3), which include major smooth-muscle-invested retinal vasculature, but the largely negative staining in the deeper scans (4–6), where smaller capillaries are more common. This is further confirmed in sections where specific Igfbp7 is shown surrounding larger vessels (7–9, inset). Staining with only secondary antibody shows no Igfbp7 staining (10–12). The American Journal of Human Genetics 2011 89, 313-319DOI: (10.1016/j.ajhg.2011.07.010) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 4 FRAM Is Characterized by Increased Signaling of the BRAF/MEK/ERK Pathway (A) IPA analysis led to the generation of a gene-interaction network of genes differentially expressed in patients. Nodes represent genes, the shape of the node represents the functional class of the gene product, and the edges indicate the biological relationship between the nodes. Green indicates downregulation, and red indicates upregulation in patients compared to controls. The color intensity is correlated with the n-fold change. (B) Upregulation of BRAF and p-ERK is confirmed at the protein level in patient lymphoblasts (family F005 II-1, II-2, and II-4, from left to right) compared to those of two controls. BRAF shows 100% increased intensity, and p-ERK shows 170% increased intensity in patients compared to two controls. The American Journal of Human Genetics 2011 89, 313-319DOI: (10.1016/j.ajhg.2011.07.010) Copyright © 2011 The American Society of Human Genetics Terms and Conditions