Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease Dong-chuan Guo, Xue-Yan Duan, Ellen.

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Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease Dong-chuan Guo, Xue-Yan Duan, Ellen S. Regalado, Lauren Mellor-Crummey, Callie S. Kwartler, Dong Kim, Kenneth Lieberman, Bert B.A. de Vries, Rolph Pfundt, Albert Schinzel, Dieter Kotzot, Xuetong Shen, Min-Lee Yang, Michael J. Bamshad, Deborah A. Nickerson, Heather L. Gornik, Santhi K. Ganesh, Alan C. Braverman, Dorothy K. Grange, Dianna M. Milewicz The American Journal of Human Genetics Volume 100, Issue 1, Pages 21-30 (January 2017) DOI: 10.1016/j.ajhg.2016.11.008 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Identification of Homozygous YY1AP1 Mutations in Grange Syndrome (A) Pedigree of family DVD047 with Grange syndrome. The age at diagnosis (dx) or death (d) in years is shown below the individual symbols. A red circle indicates the individuals who underwent exome sequencing. (B) Schematic of YY1AP1 with exons 1 through 10 (orange boxes) and the untranslated regions (UTRs; gray boxes). The YY1AP1 mutations identified in this study are indicated above the gene diagram. The brown letters indicate compound heterozygous mutations and red letters indicate homozygous mutations. The black line at the bottom of the diagram indicates the SMC isoform of YY1AP1 identified to be expressed in SMCs. (C) MR angiogram (oblique and anterior-posterior views) of individual II:7 (family DVD047) showing severe abnormalities of the cerebral vasculature with focal stenoses (thin arrow) and frank areas of discontinuity consistent with severe stenoses (thick arrow). (D) CT angiogram of individual I:2 (family DVD047) with a heterozygous YY1AP1 p.Gln242∗ variant showing stenosis of the left proximal renal artery. (E) Photographs of the proband of DVD112 with the homozygous YY1AP1 p.Gln222∗ variant showing features of Grange syndrome, including hypertelorism, brachydactyly of the fingers and toes, and fifth finger clinodactyly and mild cutaneous syndactyly of the second and third toes. The American Journal of Human Genetics 2017 100, 21-30DOI: (10.1016/j.ajhg.2016.11.008) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Characterization of YY1AP1 Protein Level and Localization in Human Smooth Muscle Cells (A) YY1AP1 is identified as an approximately 90 kDa protein in control fibroblasts; no full-length or truncated YY1AP1 protein (predicted to be 80 kDa) is present in fibroblasts explanted from an individual with Grange syndrome (DVD047; II:7). (B) YY1AP1 has a nuclear localization in SMCs and HeLa cells based on cell fractionation studies. Abbreviations: WCL, whole cell lysate; Cyto, cytoplasmic lysate; and Nuc, nuclear lysate. (C) Immunofluorescence staining with YY1AP1 antibody (green), NOP1p antibody (red), and nuclear DAPI (blue) demonstrates that in SMCs, YY1AP1 is in the nucleoplasm but also co-localizes with NOP1p in the nucleolus. (D) Hematoxylin and eosin (H&E) stain and immunohistochemical staining of YY1AP1 in control carotid artery shows YY1AP1 present in the nuclei of the SMCs between the elastic lamellae (arrowheads). Cells within the neointimal lesions in the lumen of the carotid artery (IN) and endothelial cells in the vasa vasorum (arrows) also have nuclear staining of YY1AP1. Abbreviations: IN, intima; M, media; AD, adventitia. Magnification 200×. The American Journal of Human Genetics 2017 100, 21-30DOI: (10.1016/j.ajhg.2016.11.008) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 YY1AP1 Interacts with the INO80 Chromatin Remodeling Complex (A) Western blots of whole cell lysates (WCLs) and lysates immunoprecipitated with Flag antibody (IP-Flag) from HEK293T and HEK293T cells with constitutive production of Flag-INO80E show pulldown of YY1AP1, TIP49A, and YY1 with Flag-INO80. These studies demonstrate that both YY1 and YY1AP1 associate with the INO80 complex in these cells. (B) Immunofluorescence staining of YY1AP1 and YY1 shows that both are present in the nucleoplasm of HEK293T cells. (C) Western blot of whole cell lysates (WCLs) and lysates immunoprecipitated with IgG or a YY1AP1 antibody from SMCs show pulldown of INO80C and YY1 with YY1AP1. These results demonstrate that YY1AP1 associates with the INO80 complex and YY1 in SMCs. (D) Immunofluorescence staining of YY1AP1 and YY1 shows that both are present in the nucleoplasm of SMCs, but only YY1AP1 is located in the nucleolus. The American Journal of Human Genetics 2017 100, 21-30DOI: (10.1016/j.ajhg.2016.11.008) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 4 YY1AP1 Protein Levels Are Increased after Exposure to TGF-β1 and Decreased Cellular Levels of YY1AP1 Suppress SMC Differentiation and Proliferation (A) Cellular levels of YY1AP1 are increased in SMCs in response to TGF-β1 exposure, with maximal levels at 24 hr after exposure. (B and C) The shRNAs directed against YY1AP1, C2 and C6, effectively decrease YY1AP1 levels in SMCs. Knockdown of YY1AP1 prevents increased cellular levels of SMC differentiation markers, including calponin, SM22α, and SM α-actin, after TGF-β1 treatment. Decreasing YY1AP1 in SMCs increases cellular levels of the cyclin-dependent kinase inhibitor, p21 (B), and suppresses SMC proliferation (C). Error bars represent standard deviation. (D) Flow cytometry data indicate that loss of YY1AP1 results in G2 cell cycle arrest of SMCs when compared to the control SMCs (WT). The American Journal of Human Genetics 2017 100, 21-30DOI: (10.1016/j.ajhg.2016.11.008) Copyright © 2017 American Society of Human Genetics Terms and Conditions