Philippe M. Campeau, Jaeseung C. Kim, James T. Lu, Jeremy A

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Mutations in KAT6B, Encoding a Histone Acetyltransferase, Cause Genitopatellar Syndrome Philippe M. Campeau, Jaeseung C. Kim, James T. Lu, Jeremy A. Schwartzentruber, Omar A. Abdul-Rahman, Silke Schlaubitz, David M. Murdock, Ming-Ming Jiang, Edward J. Lammer, Gregory M. Enns, William J. Rhead, Jon Rowland, Stephen P. Robertson, Valérie Cormier-Daire, Matthew N. Bainbridge, Xiang-Jiao Yang, Marie-Claude Gingras, Richard A. Gibbs, David S. Rosenblatt, Jacek Majewski, Brendan H. Lee The American Journal of Human Genetics Volume 90, Issue 2, Pages 282-289 (February 2012) DOI: 10.1016/j.ajhg.2011.11.023 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Presentation of Subjects with GPS Photographs of (A) subject 2 at 9 years of age, (B) subject 3 at 8 years of age, and (C) subject 5 at birth and at 8 months of age. The American Journal of Human Genetics 2012 90, 282-289DOI: (10.1016/j.ajhg.2011.11.023) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Hematoxylin and Eosin Images of Tissues from the Autopsy of Subject 3 Tissues shown are (A) the brain (400×) where we show a large cluster of perivascular calcifications in the white matter of the cerebral cortex (arrows point to two of them); these are never present in normal tissue; (B) the pancreas (100×) showing numerous islets of Langerhans, some of which are hyperplastic (black arrows), whereas others are of normal size (red arrows); (C) the kidney (100×), where we show one large and one small subcapsular cyst (arrows), and (D) the severely hypoplastic patella (100×), where there is persistence of the cartilaginous core of the trabeculae (black arrow). The American Journal of Human Genetics 2012 90, 282-289DOI: (10.1016/j.ajhg.2011.11.023) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Location of Mutations Identified in KAT6B The five different mutations form a cluster within the C-terminal acidic domain of KAT6B. The 16 coding exons and the corresponding introns of KAT6B are depicted with boxes and solid lines, respectively, with introns not shown to scale. The encoding domains are indicated below the exon-intron organization, along with the corresponding functions. The longest isoform is shown (isoform 1 in uniprot, a.k.a. MORF-beta, CCDS7345, 2073 aa). The following abbreviations are used: H15, histone H1- or H5-like domain; PHD, tandem plant homeodomain-linked zinc fingers. The amino acid changes resulting from five independent mutations present in 6 different subjects are indicated above the schematic exon-intronic structure. The mutations result in C-terminal truncation and remove the transcriptional activation domain, with the resulting mutant impaired in transcriptional activation. Deletions are shown in black arrows, nonsense mutations in green, and the complex insertion-deletion mutation in red. Sequence details of the mutations are shown in Table 3. The American Journal of Human Genetics 2012 90, 282-289DOI: (10.1016/j.ajhg.2011.11.023) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 Mutant Transcripts Do Not Undergo Nonsense-Mediated Decay (A) Messenger RNA levels of KAT6B, normalized to GAPDH, in lymphoblastoid cell lines derived from subjects 1–4, and from control cell lines (n = 3) (data are represented as mean ± standard error of the mean). (B) Sequencing of cDNA from those cells to demonstrate definitively that the mutant transcripts do not undergo nonsense-mediated decay. The American Journal of Human Genetics 2012 90, 282-289DOI: (10.1016/j.ajhg.2011.11.023) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 5 Myst4 Expression in Wild-Type C57BL/6 Mice Detected by Immunohistochemistry Tissues shown are (A) and (B) whole embryos at embryonic day 15.5, (C) femur at postnatal day 1, and (D) kidney at postnatal day 1. The other tissues are at 8 weeks of age: (E) patella, (F) duodenum (which required 2.5 s of exposure time instead of 5), (G) liver, (H) pancreas, (I) spleen, (J) testis, and (K) ovary. Arrows point to the telencephalic vesicles (tv), spinal cord (sc), liver, pancreas, dorsal root ganglia (drg), trigeminal ganglion (tg), ribs, and patella (pat). The American Journal of Human Genetics 2012 90, 282-289DOI: (10.1016/j.ajhg.2011.11.023) Copyright © 2012 The American Society of Human Genetics Terms and Conditions