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. 2016 Oct 6;99(4):934-941.
doi: 10.1016/j.ajhg.2016.08.001. Epub 2016 Sep 8.

De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms

Karin Weiss  1 , Paulien A Terhal  2 , Lior Cohen  3 , Michael Bruccoleri  4 , Melita Irving  5 , Ariel F Martinez  1 , Jill A Rosenfeld  6 , Keren Machol  6 , Yaping Yang  6 , Pengfei Liu  6 , Magdalena Walkiewicz  6 , Joke Beuten  6 , Natalia Gomez-Ospina  7 , Katrina Haude  8 , Chin-To Fong  8 , Gregory M Enns  7 , Jonathan A Bernstein  7 , Judith Fan  9 , Garrett Gotway  9 , Mohammad Ghorbani  4 ; DDD Study; Koen van Gassen  2 , Glen R Monroe  10 , Gijs van Haaften  10 , Lina Basel-Vanagaite  11 , Xiang-Jiao Yang  4 , Philippe M Campeau  12 , Maximilian Muenke  13
Affiliations

De Novo Mutations in CHD4, an ATP-Dependent Chromatin Remodeler Gene, Cause an Intellectual Disability Syndrome with Distinctive Dysmorphisms

Karin Weiss et al. Am J Hum Genet. .

Abstract

Chromodomain helicase DNA-binding protein 4 (CHD4) is an ATP-dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression. Also known as Mi2β, CHD4 is an integral subunit of a well-characterized histone deacetylase complex. Here we report five individuals with de novo missense substitutions in CHD4 identified through whole-exome sequencing and web-based gene matching. These individuals have overlapping phenotypes including developmental delay, intellectual disability, hearing loss, macrocephaly, distinct facial dysmorphisms, palatal abnormalities, ventriculomegaly, and hypogonadism as well as additional findings such as bone fusions. The variants, c.3380G>A (p.Arg1127Gln), c.3443G>T (p.Trp1148Leu), c.3518G>T (p.Arg1173Leu), and c.3008G>A, (p.Gly1003Asp) (GenBank: NM_001273.3), affect evolutionarily highly conserved residues and are predicted to be deleterious. Previous studies in yeast showed the equivalent Arg1127 and Trp1148 residues to be crucial for SNF2 function. Furthermore, mutations in the same positions were reported in malignant tumors, and a de novo missense substitution in an equivalent arginine residue in the C-terminal helicase domain of SMARCA4 is associated with Coffin Siris syndrome. Cell-based studies of the p.Arg1127Gln and p.Arg1173Leu mutants demonstrate normal localization to the nucleus and HDAC1 interaction. Based on these findings, the mutations potentially alter the complex activity but not its formation. This report provides evidence for the role of CHD4 in human development and expands an increasingly recognized group of Mendelian disorders involving chromatin remodeling and modification.

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Figures

Figure 1
Figure 1
Facial Dysmorphism in Subjects Harboring CHD4 Mutations From left to right: pictures of subjects 1, 2, and 5 at the age of 10 years, 12 months, and 18 years (top) and 1 year (bottom), respectively. There are similar subtle dysmorphic features that include macrocephaly, wide-spaced eyes, fullness of eyelids, a squared face, and low-set, small, or cup-shaped ears.
Figure 2
Figure 2
CHD4 Variants and Amino Acid Sequence Conservation (A) CHD4 protein domains and location of amino acid substitutions. Abbreviation: PHD, plant homeodomain zinc fingers. (B) Protein alignment of CHD4 orthologs across several vertebrate species and yeast. We also aligned with the ATP-dependent helicase SMARCA2 and SMARCA4. The Arg1127, Trp1148, and Arg1173 positions are conserved down to yeast. The p.Arg1127Gln and p.Trp1148Leu variants are located at the helicase motifs V and Vb, respectively.,
Figure 3
Figure 3
Comparison of Wild-Type and Mutant CHD4 Proteins by Cell-Based Assays (A) The two mutations do not change HDAC1 interaction. Wild-type CHD4 and the two mutants were transiently expressed in HEK293 cells as FLAG-tagged proteins with or without GFP-HDAC1. Soluble extracts were prepared ∼36 hr after transfection for immunoprecipitation (IP) on anti-FLAG antibody conjugated to agarose, and bound proteins were eluted with FLAG peptide for immunoblotting with an anti-FLAG monoclonal antibody. After extensive washing, bound proteins were eluted with FLAG peptide for immunoblotting with anti-FLAG and -GFP antibodies as indicated. HDAC1 is known to be efficiently sumoylated. (B) Mutations do not affect CHD4 nuclear localization. Wild-type CHD4 and two mutants were expressed in HEK293 cells as FLAG-tagged proteins along with a green fluorescent protein (GFP)-HDAC1 fusion protein. Cells were fixed for indirect immunofluorescence microscopy with the anti-FLAG antibody and a Cy5-conjugated secondary antibody to detect CHD4 and its mutants. Green fluorescence was used an indicator of HDAC1 levels and nuclear DNA was detected with DAPI staining. The merged images are shown at the right column. HEK293 cell transfection, indirect immunofluorescence microscopy, and immunoprecipitation were carried out as described. Note: The residual heavy chain on lane 13 is due to some anti-FLAG agarose beads that were incidentally collected when the eluate was transferred out by pipetting.
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