Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Nov 11;89(5):675-81.
doi: 10.1016/j.ajhg.2011.10.008.

Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome

Jill Clayton-Smith  1 , James O'Sullivan, Sarah Daly, Sanjeev Bhaskar, Ruth Day, Beverley Anderson, Anne K Voss, Tim Thomas, Leslie G Biesecker, Philip Smith, Alan Fryer, Kate E Chandler, Bronwyn Kerr, May Tassabehji, Sally-Ann Lynch, Malgorzata Krajewska-Walasek, Shane McKee, Janine Smith, Elizabeth Sweeney, Sahar Mansour, Shehla Mohammed, Dian Donnai, Graeme Black
Affiliations

Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome

Jill Clayton-Smith et al. Am J Hum Genet. .

Abstract

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance. A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate. The condition usually occurs sporadically and is therefore presumed to be due in most cases to new dominant mutations. In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced. Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS. Where parental samples were available, the mutations were shown to have occurred de novo. During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds. The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype. This is a further example of how perturbation of a protein involved in chromatin modification might give rise to a multisystem developmental disorder.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Clinical Phenotype, Structure, and Truncating Mutation of KAT6B (A) Photos showing clinical features of individual 10 with typical SBBYSS. Facial features include severe blepharophimosis, a bulbous nasal tip, and a mask-like appearance. The thumbs and great toes are abnormally long and straight. (B) Sanger sequencing of KAT6B in individual 4. The c.4069G>T (p.Glu1357X) mutation was absent in both parents and had arisen de novo. (C) Schematic of KAT6B including the conserved domains and position of truncating mutations. The catalytic MYST domain of the MOZ-SAS family is the histoneacetyltransferase domain and contains a specific C2HC zinc finger together with an acetyl-coenzyme A binding domain. There is a conserved N-terminal domain ([NEMM] the N-terminal domain conserved in Enok) and a highly conserved C-terminal SM-rich domain. Mutations in typical SBBYSS individuals cluster in exon 18, the final exon, and leave the catalytic domain intact. (D) KAT6B isoforms. Alternative splicing of KAT6B produces five protein coding transcripts. Three transcripts vary only in the 5′ UTR and produce the same mature protein. In-frame splicing within exon 8 results in three protein isoforms of 1781, 1890, and 2013 amino acids in length. As amino acid composition before and after exon 8 is identical in each isoform, the mutations found in exons 15 and 18 are assumed to have the same effect. White boxes indicate exons in UTR; blue boxes indicate translated exons; red box indicates exon 8; blue lines indicate introns. Mature protein contributed by exon 8 is shown in red; values indicate amino acid positions.
Figure 2
Figure 2
Morphology of Qkfgt/gt Mutant Mice and Expression of Kat6b mRNA in Tissues Affected in SBBYSS Individuals (A) Facial features including small eyes and upturned nose in a 10-month-old male Qkfgt/gt mutant mouse compared to a same-sex wild-type littermate control. (B) External appearance of a 3-week-old male Qkfgt/gt mutant mouse and a male littermate control. (C) Qkf mRNA distribution in E15.5 eyes and eyelids. Precipitated silver grains representing Qkf mRNA appear white in the darkfield image; the brightfield image is in the adjacent panel. (D) Qkf mRNA distribution in E15.5 tooth primordia. (E) β-galactosidase reporter staining (blue) indicates high-expression activity of the Qkf locus in the developing hindlimb at the stages indicated. (F) Feet of a 3-week-old male Qkfgt/gt mutant mouse and a male littermate control. Note the long and slender appearance of the Qkfgt/gt foot and digits. The following abbreviations are used: I to V, digits I to V of the hindlimb; EL, eyelids; Le, lens; To, tongue; TP, tooth primordium; Re, retina. The scale bars (C and D) equal 133 μm. Embryo recovery, histological processing and sectioning, radioactive in situ hybridization, and β-galactosidase staining were performed as previously published., ,
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

  • De novo mutations in MLL cause Wiedemann-Steiner syndrome.
    Jones WD, Dafou D, McEntagart M, Woollard WJ, Elmslie FV, Holder-Espinasse M, Irving M, Saggar AK, Smithson S, Trembath RC, Deshpande C, Simpson MA. Jones WD, et al. Am J Hum Genet. 2012 Aug 10;91(2):358-64. doi: 10.1016/j.ajhg.2012.06.008. Epub 2012 Jul 12. Am J Hum Genet. 2012. PMID: 22795537 Free PMC article.
  • Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants.
    Zhang LX, Lemire G, Gonzaga-Jauregui C, Molidperee S, Galaz-Montoya C, Liu DS, Verloes A, Shillington AG, Izumi K, Ritter AL, Keena B, Zackai E, Li D, Bhoj E, Tarpinian JM, Bedoukian E, Kukolich MK, Innes AM, Ediae GU, Sawyer SL, Nair KM, Soumya PC, Subbaraman KR, Probst FJ, Bassetti JA, Sutton RV, Gibbs RA, Brown C, Boone PM, Holm IA, Tartaglia M, Ferrero GB, Niceta M, Dentici ML, Radio FC, Keren B, Wells CF, Coubes C, Laquerrière A, Aziza J, Dubucs C, Nampoothiri S, Mowat D, Patel MS, Bracho A, Cammarata-Scalisi F, Gezdirici A, Fernandez-Jaen A, Hauser N, Zarate YA, Bosanko KA, Dieterich K, Carey JC, Chong JX, Nickerson DA, Bamshad MJ, Lee BH, Yang XJ, Lupski JR, Campeau PM. Zhang LX, et al. Genet Med. 2020 Aug;22(8):1338-1347. doi: 10.1038/s41436-020-0811-8. Epub 2020 May 19. Genet Med. 2020. PMID: 32424177 Free PMC article. Review.
  • Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations.
    Basel-Vanagaite L, Yilmaz R, Tang S, Reuter MS, Rahner N, Grange DK, Mortenson M, Koty P, Feenstra H, Farwell Gonzalez KD, Sticht H, Boddaert N, Désir J, Anyane-Yeboa K, Zweier C, Reis A, Kubisch C, Jewett T, Zeng W, Borck G. Basel-Vanagaite L, et al. Hum Genet. 2014 Jul;133(7):939-49. doi: 10.1007/s00439-014-1436-2. Epub 2014 Mar 11. Hum Genet. 2014. PMID: 24615390
  • Genitopatellar syndrome: the first reported case in Japan.
    Okano S, Miyamoto A, Fukuda I, Tanaka H, Hata K, Kaname T, Matsubara Y, Makita Y. Okano S, et al. Hum Genome Var. 2018 May 28;5:8. doi: 10.1038/s41439-018-0010-1. eCollection 2018. Hum Genome Var. 2018. PMID: 29899993 Free PMC article.
  • The Chromatin Regulator BRPF3 Preferentially Activates the HBO1 Acetyltransferase but Is Dispensable for Mouse Development and Survival.
    Yan K, You L, Degerny C, Ghorbani M, Liu X, Chen L, Li L, Miao D, Yang XJ. Yan K, et al. J Biol Chem. 2016 Feb 5;291(6):2647-63. doi: 10.1074/jbc.M115.703041. Epub 2015 Dec 16. J Biol Chem. 2016. PMID: 26677226 Free PMC article.
See all "Cited by" articles

References

    1. Verloes A., Bremond-Gignac C., Isidor B., David A., Baumann C., Leroy M.A., Stevens R., Gillerot Y., Héron D., Héron B., et al. Blepharophimosis-mental retardation syndromes: A proposed clinical classification of the so-called Ohdo syndrome, and delineation of two new BMR syndromes, one X-linked and one autosomal recessive. Am. J. Med. Genet. A. 2006;140:1285–1296. - PubMed
    1. Ohdo S., Madokoro H., Sonoda T., Hayakawa K. Mental retardation associated with congenital heart disease, blepharophimosis, blepharoptosis, and hypoplastic teeth. J. Med. Genet. 1986;23:242–244. - PMC - PubMed
    1. Say B., Barber N. Mental retardation with blepharophimosis. J. Med. Genet. 1987;24:511. - PMC - PubMed
    1. Biesecker L.G. The Ohdo blepharophimosis syndrome: a third case. J. Med. Genet. 1991;28:131–134. - PMC - PubMed
    1. Young I.D., Simpson K. Unknown syndrome: abnormal facies, congenital heart defects, hypothyroidism, and severe retardation. J. Med. Genet. 1987;24:715–716. - PMC - PubMed

Publication types

MeSH terms

Supplementary concepts