Molecular Genetics of Kabuki Syndrome


Kabuki syndrome (KS) is a rare, multiple congenital anomalies/mental retardation syndrome characterised by a peculiar face, skeletal abnormalities, cardiac anomalies, and immunological defects. Exome sequencing identified MLL2 mutations as a major cause of KS. MLL2 is a member of the Mixed Lineage Leukaemia (MLL) family of histone methyltransferases, essential in the epigenetic control of active chromatin states. MLLs act as transcriptional co‐activators in embryogenesis and development. As a significant proportion of patients do not have any MLL2 mutation, the existence of additional genes associated with this syndrome was postulated. By Comparative Genomic Hybridisation (CGH) array, de novo partial and/or complete deletions of KDM6A gene have been identified in a small group of MLL2‐mutation‐negative Kabuki patients. Notably, KDM6A codes a histone demethylase that interacts with MLL2. Overall, these findings suggest that Kabuki syndrome is a genetic heterogeneity disease and highlights the growing role of histone methylases and histone demethylases in multiple congenital anomalies and intellectual‐disability syndromes.

Key Concepts:

  • Kabuki syndrome is a rare, multiple malformation disorder characterised by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability.

  • Kabuki syndrome is an autosomal dominant condition that de novo arises in the majority of patients. It is phenotypically variable and genetically heterogeneous.

  • Whole exome sequencing identified mutations in MLL2 gene in approximately 70% of the Kabuki patients.

  • The MLL2 gene encodes a multiple domain‐containing protein that methylates the Lys‐4 position of histone H3 (H3K4), an epigenetic mark correlated with transcriptional active chromatin.

  • Approximately 70% of MLL2 mutation‐positive KS patients carry truncating mutations predicted to result in haploinsufficiency or nonfunctional MLL2 protein.

  • In a search for an additional gene causing Kabuki syndrome, microdeletions of the KDM6A gene were identified in three MLL2‐mutation‐negative Kabuki patients.

  • KDM6A is a histone demethylases that interacts with MLL2.

  • Histone methylases and histone demethylases are key‐genes involved in multiple congenital anomalies and intellectual‐disability syndromes.

Keywords: Kabuki syndrome; Histone Methyltransferase; HOX genes; MLL2; KDM6A; chromatin remodelling; sequencing; CGH array; mutation

Figure 1.

Schematic representation of MLL2 and KDM6A protein domains. (a) MLL2 protein domain structures. PHD, plant homeodomain finger; HMG‐box, high mobility group; CC, Coiled Coil; LXXLL domain; FYRN, FY‐rich domain, N‐terminal region; FYRC, FY‐rich domain, C‐terminal region; SET, (Su(var)3‐9, Enhancer‐of‐zeste, Trithorax) domain; PostSET: PostSET domain. (b) KDM6A protein domains. TPR, tetratricopeptide repeat; LR, linker region; HD, helical domain; JmjC, JumonjiC catalytic domain; ZnBD, Zinc binding domain. The helical and Zn‐binding domains, together with the Jmj domain, comprise the KDM6A catalytic domain.

Figure 2.

MLL2 histone H3K4 methylase and KDM6A histone H3K27 demethylase activity. The basic unit of chromatin, the nucleosome, consists of 146 bp of DNA wrapped around a histone octamer, which is composed of two copies of each of the four core histones: H2A, H2B, H3 and H4. One such covalent modification of core histones is methylation, which occurs on arginine and lysine residues, and is involved in regulating a wide range of processes including gene activity, chromatin structure, dosage compensation and epigenetic memory. In general, lysine (K) methylation at H3K9, H3K27 and H4K20 is associated with regions of transcriptionally silenced chromatin, whereas methylation at H3K4, H3K36 and H3K79 is associated with transcriptionally active regions. MLL2 regulates cellular H3K4 methylation levels; KDM6A has been shown to reverse H3K27 di‐ trimethylation. Ubiquitination of H2AK119 and H2BK120 are correlated to the active chromatin state.

Figure 3.

Different MLL2 mutation types in Kabuki syndrome patients. Frequency of the MLL2 types of mutations so far identified in Ng et al. , Paulussen et al. , Li et al. , Micale et al. , Hannibal et al. and Banka et al. studies.



Ansari KI, Hussain I, Shrestha B, Kasiri S and Mandal SS (2011) HOXC6 is transcriptionally regulated via coordination of MLL histone methylase and estrogen receptor in an estrogen environment. Journal of Molecular Biology 411: 334–349.

Ansari KI and Mandal SS (2010) Mixed lineage leukemia: roles in gene expression, hormone signaling and mRNA processing. FEBS Journal 277: 1790–1804.

Aziz A, Liu QC and Dilworth FJ (2010) Regulating a master regulator: establishing tissue‐specific gene expression in skeletal muscle. Epigenetics 5: 691–695.

Banka S, Veeramachaneni R, Reardon W et al. (2012) How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum. European Journal of Human Genetics 20(4): 381–388.

Caslini C, Connelly JA, Serna A, Broccoli D and Hess JL (2009) MLL associates with telomeres and regulates telomeric repeat‐containing RNA transcription. Molecular and Cellular Biology 29: 4519–4526.

Choufani S, Shuman C and Weksberg R (2011) Beckwith–Wiedemann syndrome. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 154C: 343–354.

Courtens W, Rassart A, Stene JJ and Vamos E (2000) Further evidence for autosomal dominant inheritance and ectodermal abnormalities in Kabuki syndrome. American Journal of Medical Genetics 93: 244–249.

Cusco I, del Campo M, Vilardell M et al. (2008) Array‐CGH in patients with Kabuki‐like phenotype: identification of two patients with complex rearrangements including 2q37 deletions and no other recurrent aberration. BMC Medical Genetics 9: 27.

Davis MB, SanGil I, Berry G, Olayokun R and Neves LH (2011) Identification of common and cell type specific LXXLL motif EcR cofactors using a bioinformatics refined candidate RNAi screen in Drosophila melanogaster cell lines. BMC Developmental Biology 11: 66.

Deroo BJ and Korach KS (2006) Estrogen receptors and human disease. Journal of Clinical Investigation 116: 561–570.

Dillon SC, Zhang X, Trievel RC and Cheng X (2005) The SET‐domain protein superfamily: protein lysine methyltransferases. Genome Biology 6: 227.

Dou Y, Milne TA, Ruthenburg AJ et al. (2006) Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nature Structural & Molecular Biology 13: 713–719.

Dreijerink KM, Mulder KW, Winkler GS et al. (2006) Menin links estrogen receptor activation to histone H3K4 trimethylation. Cancer Research 66: 4929–4935.

Eggermann T, Begemann M, Spengler S et al. (2011) Genetic and epigenetic findings in Silver–Russell syndrome. Pediatric Endocrinology Reviews 8: 86–93.

Eissenberg JC and Shilatifard A (2010) Histone H3 lysine 4 (H3K4) methylation in development and differentiation. Developmental Biology 339: 240–249.

Garcia‐Alai MM, Allen MD, Joerger AC and Bycroft M (2010) The structure of the FYR domain of transforming growth factor beta regulator 1. Protein Science 19: 1432–1438.

Hannibal MC, Buckingham KJ, Ng SB et al. (2011) Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome. American Journal of Medical Genetics Part A 155A: 1511–1516.

Herz HM, Madden LD, Chen Z et al. (2010) The H3K27me3 demethylase dUTX is a suppressor of Notch‐ and Rb‐dependent tumors in Drosophila. Molecular and Cellular Biology 30: 2485–2497.

Ho HH and Eaves LC (1997) Kabuki make‐up (Niikawa–Kuroki) syndrome: cognitive abilities and autistic features. Developmental Medicine & Child Neurology 39: 487–490.

Hoischen A, van Bon BW, Gilissen C et al. (2010) De novo mutations of SETBP1 cause Schinzel–Giedion syndrome. Nature Genetics 42: 483–485.

Hong S, Cho YW, Yu LR et al. (2007) Identification of JmjC domain‐containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proceedings of the National Academy of Sciences of the USA 104: 18439–18444.

Hughes CL, Liu PZ and Kaufman TC (2004) Expression patterns of the rogue Hox genes Hox3/zen and fushi tarazu in the apterygote insect Thermobia domestica. Evolution & Development 6: 393–401.

Iimura T and Pourquie O (2007) Hox genes in time and space during vertebrate body formation. Development, Growth & Differentiation 49: 265–275.

Issaeva I, Zonis Y, Rozovskaia T et al. (2007) Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Molecular and Cellular Biology 27: 1889–1903.

Jenuwein T, Laible G, Dorn R and Reuter G (1998) SET domain proteins modulate chromatin domains in eu‐ and heterochromatin. Cellular and Molecular Life Sciences 54: 80–93.

Jones RS and Gelbart WM (1993) The Drosophila Polycomb‐group gene enhancer of zeste contains a region with sequence similarity to trithorax. Molecular and Cellular Biology 13: 6357–6366.

Kleefstra T, Brunner HG, Amiel J et al. (2006) Loss‐of‐function mutations in euchromatin histone methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric deletion syndrome. American Journal of Human Genetics 79: 370–377.

Klose RJ, Yamane K, Bae Y et al. (2006) The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36. Nature 442: 312–316.

Kuroki Y, Suzuki Y, Chyo H, Hata A and Matsui I (1981) A new malformation syndrome of long palpebral fissures, large ears, depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation. Journal of Pediatrics 99: 570–573.

Lan F, Bayliss PE, Rinn JL et al. (2007) A histone H3 lysine 27 demethylase regulates animal posterior development. Nature 449: 689–694.

Lederer D, Grisart B, Digilio MC et al. (2012) Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. American Journal of Medical Genetics 90: 119–124.

Lee MG, Villa R, Trojer P et al. (2007) Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318: 447–450.

Li Y, Bogershausen N, Alanay Y et al. (2011) A mutation screen in patients with Kabuki syndrome. Human Genetics 130: 715–724.

Malik S and Bhaumik SR (2010) Mixed lineage leukemia: histone H3 lysine 4 methyltransferases from yeast to human. FEBS Journal 277: 1805–1821.

Micale L, Augello B, Fusco C et al. (2011) Mutation spectrum of MLL2 in a cohort of Kabuki syndrome patients. Orphanet Journal of Rare Diseases 6: 38.

Miller SA, Mohn SE and Weinmann AS (2010) Jmjd3 and UTX play a demethylase‐independent role in chromatin remodeling to regulate T‐box family member‐dependent gene expression. Molecular Cell 40: 594–605.

Mo R, Rao SM and Zhu YJ (2006) Identification of the MLL2 complex as a coactivator for estrogen receptor alpha. Journal of Biological Chemistry 281: 15714–15720.

Mosammaparast N and Shi Y (2011) Reversal of histone methylation: biochemical and molecular mechanisms of histone demethylases. Annual Review of Biochemistry 79: 155–179.

Ng SB, Bigham AW, Buckingham KJ et al. (2010) Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nature Genetics 42: 790–793.

Niikawa N, Matsuura N, Fukushima Y, Ohsawa T and Kajii T (1981) Kabuki make‐up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. Journal of Pediatrics 99: 565–569.

Oksanen VE, Arvio MA, Peippo MM, Valanne LK and Sainio KO (2004) Temporo‐occipital spikes: a typical EEG finding in Kabuki syndrome. Pediatric Neurology 30: 67–70.

Pasini D, Bracken AP, Agger K et al. (2008) Regulation of stem cell differentiation by histone methyltransferases and demethylases. Cold Spring Harbor Symposia on Quantitative Biology 73: 253–263.

Paulussen AD, Stegmann AP, Blok MJ et al. (2011) MLL2 mutation spectrum in 45 patients with Kabuki syndrome. Human Mutation 32: E2018–2025.

Say B, McCutcheon L, Todd C and Hough JV (1993) Kabuki make‐up syndrome and hearing impairment. Clinical Dysmorphology 2: 68–70.

Schuettengruber B, Chourrout D, Vervoort M, Leblanc B and Cavalli G (2007) Genome regulation by polycomb and trithorax proteins. Cell 128: 735–745.

Seenundun S, Rampalli S, Liu QC et al. (2010) UTX mediates demethylation of H3K27me3 at muscle‐specific genes during myogenesis. EMBO Journal 29: 1401–1411.

Shi Y, Lan F, Matson C et al. (2004) Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119: 941–953.

Stassen MJ, Bailey D, Nelson S, Chinwalla V and Harte PJ (1995) The Drosophila trithorax proteins contain a novel variant of the nuclear receptor type DNA binding domain and an ancient conserved motif found in other chromosomal proteins. Mechanisms of Development 52: 209–223.

Tschiersch B, Hofmann A, Krauss V et al. (1994) The protein encoded by the Drosophila position‐effect variegation suppressor gene Su(var)3‐9 combines domains of antagonistic regulators of homeotic gene complexes. EMBO Journal 13: 3822–3831.

Tsukada Y, Fang J, Erdjument‐Bromage H et al. (2006) Histone demethylation by a family of JmjC domain‐containing proteins. Nature 439: 811–816.

Wang P, Lin C, Smith ER et al. (2009) Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1‐mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. Molecular and Cellular Biology 29: 6074–6085.

Further Reading

Adam MP and Hudgins L (2005) Kabuki syndrome: a review. Clinical Genetics 67: 209–219.

Cosgrove MS and Patel A (2010) Mixed lineage leukemia: a structure‐function perspective of the MLL1 protein. FEBS Journal 277: 1832–1842.

Gibney ER and Nolan CM (2010) Epigenetics and gene expression. Heredity (Edinb) 105: 4–13.

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Micale, Lucia, and Merla, Giuseppe(May 2012) Molecular Genetics of Kabuki Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023848]