De Novo Nonsense Mutations in KAT6A, a Lysine Acetyl-Transferase Gene, Cause a Syndrome Including Microcephaly and Global Developmental Delay Valerie A.

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De Novo Nonsense Mutations in KAT6A, a Lysine Acetyl-Transferase Gene, Cause a Syndrome Including Microcephaly and Global Developmental Delay Valerie A. Arboleda, Hane Lee, Naghmeh Dorrani, Neda Zadeh, Mary Willis, Colleen Forsyth Macmurdo, Melanie A. Manning, Andrea Kwan, Louanne Hudgins, Florian Barthelemy, M. Carrie Miceli, Fabiola Quintero-Rivera, Sibel Kantarci, Samuel P. Strom, Joshua L. Deignan, Wayne W. Grody, Eric Vilain, Stanley F. Nelson The American Journal of Human Genetics Volume 96, Issue 3, Pages 498-506 (March 2015) DOI: 10.1016/j.ajhg.2015.01.017 Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 1 Location of Mutations in KAT6A (A) Pedigrees of families 1–4. (B) Photos of probands 1-II-1, 2-II-2, and 4-II-1 depict the characteristic eye and nasal features observed in KAT6A syndrome. (C) KAT6A is located at 8p11.2. All four de novo mutations are located in exons 16 and 17 (arrows) that are predicted to lead to a truncated protein (red arrowheads) that is missing most of the acidic (orange) and the Serine- and Methionine-rich domains (yellow); NEMM, N-terminal part of Enok, MOZ, or MORF; PHD, Plant homeodomain-linked zinc finger; HAT, Histone Acetyltransferase. (D) Sequence traces of KAT6A from genomic DNA of Proband 1-II-1 demonstrates the p.Arg1129∗ variant and Proband 3-II-1 demonstrates the p.Arg1024∗ variant. The American Journal of Human Genetics 2015 96, 498-506DOI: (10.1016/j.ajhg.2015.01.017) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 2 KAT6A Mutations Do Not Undergo Nonsense-Mediated Decay (A) RNA from control (ATCC), proband 1-II-1 and proband 3-II-1 dermal fibroblasts were amplified and sequenced by capillary electrophoresis. The mutation in proband 1-II-1 in the last exon of KAT6A showed equal presence of the WT and mutant transcript. The mutation in proband 3-II-1 showed allelic preference for the reference allele. (B) Quantitative real-time PCR in fibroblasts from proband 1-II-1 and 3-II-1 showed no significant decrease in KAT6A mRNA compared to control fibroblast samples. All samples were run triplicate and normalized against GAPDH. All samples were compared to biological controls and the (2(-ddCt)) method was used for statistical analysis. The American Journal of Human Genetics 2015 96, 498-506DOI: (10.1016/j.ajhg.2015.01.017) Copyright © 2015 The American Society of Human Genetics Terms and Conditions

Figure 3 KAT6A Nonsense Mutations Result in Global Changes in Histone Acetylation and p53 Signaling Pathways (A) H3K9 acetylation was decreased in histone extracts from proband 1-II-1 dermal fibroblasts relative to control. H3K18 acetylation was increased in proband 1-II-1 dermal fibroblasts compared to control. All experiments were performed in duplicate. (B) Genes in the P53 signaling pathway that show significant differences between experimental (Proband 1-II-1 or Proband 3-II-1) and control fibroblasts growing in culture were assessed using RNaseq. All genes shown were significantly increased or decreased if the q value was less than the FDR-adjusted p value of the test statistic. The American Journal of Human Genetics 2015 96, 498-506DOI: (10.1016/j.ajhg.2015.01.017) Copyright © 2015 The American Society of Human Genetics Terms and Conditions