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, ; 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.



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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]