CHARGE and Kabuki syndromes: a phenotypic and molecular link.

Abstract

CHARGE syndrome is a complex developmental disorder caused by mutations in the chromodomain helicase DNA-binding gene CHD7. Kabuki syndrome, another developmental disorder, is characterized by typical facial features in combination with developmental delay, short stature, prominent digit pads and visceral abnormalities. Mutations in the KMT2D gene, which encodes a H3K4 histone methyltransferase, are the major cause of Kabuki syndrome. Here, we report a patient, who was initially diagnosed with CHARGE syndrome based on the spectrum of inner organ malformations like choanal hypoplasia, heart defect, anal atresia, vision problems and conductive hearing impairment. While sequencing and MLPA analysis of all coding exons of CHD7 revealed no pathogenic mutation, sequence analysis of the KMT2D gene identified the heterozygous de novo nonsense mutation c.5263C > T (p.Gln1755*). Thus, our patient was diagnosed with Kabuki syndrome. By using co-immunoprecipitation, immunohistochemistry and direct yeast two hybrid assays, we could show that, like KMT2D, CHD7 interacts with members of the WAR complex, namely WDR5, ASH2L and RbBP5. We therefore propose that CHD7 and KMT2D function in the same chromatin modification machinery, thus pointing out a mechanistic connection, and presenting a probable explanation for the phenotypic overlap between Kabuki and CHARGE syndromes.

• Authors: Yvonne Schulz, Luisa Freese, Johanna Mänz, Barbara Zoll, Christiane Völter, Knut Brockmann, Nina Bögershausen, Jutta Becker, Bernd Wollnik, Silke Pauli
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 23 Issue 16 Pg. 4396-405 (Aug 15 2014) ISSN: 1460-2083 [Electronic] England
• PMID: 24705355 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Ash2l protein, mouse
• DNA-Binding Proteins
• Intracellular Signaling Peptides and Proteins
• KMT2D protein, human
• Neoplasm Proteins
• Nuclear Proteins
• Proteins
• RBBP5 protein, mouse
• Transcription Factors
• Wdr5 protein, mouse
• DNA Helicases
• CHD7 protein, human

Topics

• Abnormalities, Multiple (genetics, metabolism, pathology)
• CHARGE Syndrome (genetics, metabolism, pathology)
• Child
• DNA Helicases (genetics, metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Face (abnormalities, pathology)
• HeLa Cells (cytology)
• Hematologic Diseases (genetics, metabolism, pathology)
• Humans
• Intracellular Signaling Peptides and Proteins
• Male
• Mutation
• Neoplasm Proteins (genetics, metabolism)
• Nuclear Proteins (metabolism)
• Phenotype
• Proteins (metabolism)
• Transcription Factors (metabolism)
• Vestibular Diseases (genetics, metabolism, pathology)