Jennifer J. Johnston, Monica Y. Sanchez-Contreras, Kim M

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A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome Jennifer J. Johnston, Monica Y. Sanchez-Contreras, Kim M. Keppler-Noreuil, Julie Sapp, Molly Crenshaw, NiCole A. Finch, Valerie Cormier-Daire, Rosa Rademakers, Virginia P. Sybert, Leslie G. Biesecker The American Journal of Human Genetics Volume 97, Issue 3, Pages 465-474 (September 2015) DOI: 10.1016/j.ajhg.2015.07.009 Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 1 Individual 1 at the Age of 29 Years (A and B) He had sparse and blond hair, bitemporal prominences, and closely spaced eyes. He had a long nose with a convex ridge, a narrow philtrum, and retrognathia. (C and D) He had severe contractures and shortening of his fingers and toes with small, broad, and thick toenails. The nodules and scar-like lesions on the hands, feet, and elbows reported earlier in life had resolved, although the individual had thin skin with prominent venous patterning and hyperkeratotic palms and soles with significant callus formation on the soles. The American Journal of Human Genetics 2015 97, 465-474DOI: (10.1016/j.ajhg.2015.07.009) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 2 Individual 3 at the Age of 7 Years (A) He had distinctive facies with thin hair, sparse eyebrows, widely spaced eyes, long palpebral fissures, a narrow nasal bridge, malar flattening, and prognathism. His skin was thin. (B) He had broad fingers with short, broad distal phalanges with hypertrophic scars. The American Journal of Human Genetics 2015 97, 465-474DOI: (10.1016/j.ajhg.2015.07.009) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 3 Individual 4 at the Ages of 6 and 14 Years She is 6 years of age in (A) and (B) and 14 years of age in (C) and (D). The views of her limbs at these two time points illustrate the severity of the progression in this individual. She had short hands and feet with small distal phalanges. There were star-shaped scar-like lesions on her palms and horizontal linear bands of thickened skin on the dorsum of her hands and tops of her feet. Dermatoglyphics were absent, and there was thickened skin at the ends of the digits. She had linear areas of thickened skin and pseudopodia of the feet. Her skin was dry, thickened, and hyperkeratotic, but the vascular pattern was normal. The American Journal of Human Genetics 2015 97, 465-474DOI: (10.1016/j.ajhg.2015.07.009) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 4 Expression of Total PDGFRB Receptor in HeLa Cells Transfected with WT, p.Leu658Pro, and p.Val665Ala PDGFRB Constructs Representative western blots showing total PDGFRB (A), phosphorylated PDGFRB at tyrosine 751 (p-Tyr751) (B), and tyrosine 1021 (p-Tyr1021) (C) of the WT (wild-type), p.Leu658Pro, and p.Val665Ala variants. α-tubulin is shown as a protein loading control (D). Horizontal bars indicate the electrophoretic mobility of three mature forms of PDGFRB (180, 160, and 130 kDa) (E). Quantitative analysis of the three mature forms of total PDGFRB was observed by western blot (n = 3). Values represent the percentage (average ± S.E.M.) of each PDGFRB form from the total PDGFRB in WT cells. ∗∗∗ = p < 0.001, ∗∗∗∗ = p < 0.0001. ns, non-significant. The American Journal of Human Genetics 2015 97, 465-474DOI: (10.1016/j.ajhg.2015.07.009) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 5 Time Course for the Phosphorylation of WT and p.Val665Ala PDGFRB Receptors Representative western blots of transfected HeLa cells treated with PDGF-BB at 5, 15, 30, and 60 min and blotted to detect total PDGFRB (A), phosphorylated PDGFRB at tyrosine 751 (p-Tyr751) (B), and tyrosine 1021 (p-Tyr1021) (C). Horizontal bars indicate the electrophoretic mobility of the two main PDGFRB forms (180 and 160 kDa) (D). Schematic representation of the quantitative data obtained by western blot of the time-dependent change in the PDGF-BB-induced phosphorylation of PDGFRB (n = 3). Data are expressed as the fold change (average ± SEM) in p-Tyr751 and p-Tyr1021 immunoreactivity at 180 and 160 kDa bands compared to the corresponding band of total PDGFRB. ∗ = p < 0.05, ∗∗ = p < 0.01, ∗∗∗ = p < 0.001, ∗∗∗∗ = p < 0.0001. The American Journal of Human Genetics 2015 97, 465-474DOI: (10.1016/j.ajhg.2015.07.009) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 6 Time Course for the Phosphorylation of PDGFRB Downstream Signaling Molecules in HeLa Cells Transfected with WT and p.Val665Ala Constructs Representative western blots of transfected HeLa cells treated with PDGF-BB at 5, 15, 30 and 60 min blotted to detect phosphorylated AKT (pAKT) and total AKT (A), phosphorylated STAT3 (pSTAT3) and total STAT3 (B), phosphorylated PLCγ1 (pPLCγ1) and total PLCγ1 (C), phosphorylated SRC (pSRC) and total SRC (D), and phosphorylated ERK (pERK) and total ERK (E). α-tubulin is shown as a protein loading control (F). Molecular size is indicated in kDa. A schematic representation of the quantitative data obtained by western blot of the time-dependent change in the PDGF-BB-induced phosphorylation of AKT, STAT3, PLCγ1, SRC, and ERK is shown at the right of the corresponding blots (n = 3). Data are expressed as the fold change (average ± SEM) in pAKT, pSTAT3, pPLCγ1, pSRC, and pERK in comparison to total AKT, STAT3, PLCγ, SRC, and ERK, respectively. ∗ = p < 0.05, ∗∗ = p < 0.01. The American Journal of Human Genetics 2015 97, 465-474DOI: (10.1016/j.ajhg.2015.07.009) Copyright © 2015 The American Society of Human Genetics Terms and Conditions