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. 2014 Jun 1;23(11):2888-900.
doi: 10.1093/hmg/ddu002. Epub 2014 Jan 8.

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Frank J Kaiser  1 , Morad Ansari, Diana Braunholz, María Concepción Gil-Rodríguez, Christophe Decroos, Jonathan J Wilde, Christopher T Fincher, Maninder Kaur, Masashige Bando, David J Amor, Paldeep S Atwal, Melanie Bahlo, Christine M Bowman, Jacquelyn J Bradley, Han G Brunner, Dinah Clark, Miguel Del Campo, Nataliya Di Donato, Peter Diakumis, Holly Dubbs, David A Dyment, Juliane Eckhold, Sarah Ernst, Jose C Ferreira, Lauren J Francey, Ulrike Gehlken, Encarna Guillén-Navarro, Yolanda Gyftodimou, Bryan D Hall, Raoul Hennekam, Louanne Hudgins, Melanie Hullings, Jennifer M Hunter, Helger Yntema, A Micheil Innes, Antonie D Kline, Zita Krumina, Hane Lee, Kathleen Leppig, Sally Ann Lynch, Mark B Mallozzi, Linda Mannini, Shane McKee, Sarju G Mehta, Ieva Micule; Care4Rare Canada Consortium; Shehla Mohammed, Ellen Moran, Geert R Mortier, Joe-Ann S Moser, Sarah E Noon, Naohito Nozaki, Luis Nunes, John G Pappas, Lynette S Penney, Antonio Pérez-Aytés, Michael B Petersen, Beatriz Puisac, Nicole Revencu, Elizabeth Roeder, Sulagna Saitta, Angela E Scheuerle, Karen L Schindeler, Victoria M Siu, Zornitza Stark, Samuel P Strom, Heidi Thiese, Inga Vater, Patrick Willems, Kathleen Williamson, Louise C Wilson; University of Washington Center for Mendelian Genomics; Hakon Hakonarson, Fabiola Quintero-Rivera, Jolanta Wierzba, Antonio Musio, Gabriele Gillessen-Kaesbach, Feliciano J Ramos, Laird G Jackson, Katsuhiko Shirahige, Juan Pié, David W Christianson, Ian D Krantz, David R Fitzpatrick, Matthew A Deardorff
Affiliations

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance

Frank J Kaiser et al. Hum Mol Genet. .

Abstract

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

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Figures

Figure 1.
Figure 1.
Mutations in HDAC8. (A) Copy number abnormalities that disrupt the HDAC8 locus. Localization of deletions (red) and duplications (blue) on Xq13 are indicated by chromosome band and position (hg19). Gene locations are indicated in blue with gene names. HDAC8 is indicated in bold. (B) Localization of HDAC8 missense mutations on the crystal structure (PDB accession code 2V5W (27)). Mutated residues are in red and labeled. The acetylated substrate is in gray and the active site zinc ion (Zn) is in dark blue. The light blue portion indicates the L2 substrate-binding loop. Green and purple tubes indicate the catalytically important main and branch exit channels, respectively, for the acetate hydrolysis product (28,29). (C) HDAC8 mutations disrupt deacetylase activity. Bar graphs demonstrate the effect of HDAC8 mutations on deacetylase relative activity relative to the wild-type enzyme activity (specific activities are noted in Supplementary Material, Table S1). All assays were performed in triplicate. Error bars indicate standard deviation. Enzymatic activity for all mutations is significantly less than wild type (P <0.05) using a two-tailed unpaired t-test. Single letter amino acids are used for mutation notation to correlate with residues in (B and C). (D) Conservation of mutations in HDAC8. Alignment of HDAC8 and related deacetylases from 10 species, as indicated on the left. Residues identical to the human residue in a majority of species at each position are in bold, in dark gray and a black border. Those that are similar are shaded in lighter gray, without a border. Each mutated human residue is indicated at the top, with a yellow box surrounding the aligned residues. Note the conservation through yeast for all residues in which a missense mutation causes a complete loss of function.
Figure 2.
Figure 2.
Individuals with HDAC8 mutations. Facial features of individuals with HDAC8 mutations labeled with corresponding mutation and sex; ♂, male; ♀, female. Photos for individual patients are grouped, with the first image for each containing the type of mutation and sex, and the last image containing the subject identifier.
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References

    1. Bhuiyan Z., Klein M., Hammond P., Mannens M.M., Van Haeringen A., Van Berckelaer-Onnes I., Hennekam R.C. Genotype–phenotype correlations of 39 patients with Cornelia de Lange syndrome: the Dutch experience. J. Med. Genet. 2005;43:568–575. - PMC - PubMed
    1. Gillis L.A., McCallum J., Kaur M., DeScipio C., Yaeger D., Mariani A., Kline A.D., Li H.H., Devoto M., Jackson L.G., et al. NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations. Am. J. Hum. Genet. 2004;75:610–623. - PMC - PubMed
    1. Krantz I.D., McCallum J., DeScipio C., Kaur M., Gillis L.A., Yaeger D., Jukofsky L., Wasserman N., Bottani A., Morris C.A., et al. Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat. Genet. 2004;36:631–635. - PMC - PubMed
    1. Tonkin E.T., Wang T.J., Lisgo S., Bamshad M.J., Strachan T. NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat. Genet. 2004;36:636–641. - PubMed
    1. Yan J., Saifi G.M., Wierzba T.H., Withers M., Bien-Willner G.A., Limon J., Stankiewicz P., Lupski J.R., Wierzba J. Mutational and genotype-phenotype correlation analyses in 28 Polish patients with Cornelia de Lange syndrome. Am. J. Med. Genet. A. 2006;140:1531–1541. - PubMed

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