CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities1. Despite 70–90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood2. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p5325,26,53,54)3, along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p5325,26,53,54 mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p5325,26,53,54/− embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.

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We thank S. Spano-Mello, K. T. Bieging, N. Raj and M. Monje-Deisseroth for reading the manuscript and S. E. Artandi and T. Williams for discussion. We thank H. Chou for immunohistochemistry assistance; E. L. Van Nostrand, P. Lavori, and A. McMillian for statistical analysis; K. Weinberg and D. Min for thymus analysis assistance; M. Shkreli for kidney analysis assistance; B. Liu and J. A. Helms for craniofacial analysis assistance; and M. Bowen for Chd7 mouse experiment assistance. We thank S. E. Artandi for plasmids; S. E. Artandi and P. Khavari for control human fibroblast cell lines; D. Lane and B. Vojtesek for wild-type p53-specific antibody (pAB242); P. Scacheri for wild-type and Chd7-null mouse embryonic stem cells; and T. Denecker and G. Goudefroye for TP53 sequencing in patients. This work was supported by funding from the NSF and NCI (grant number 1F31CA167917-01) to J.L.V.N.; from the NIH (RO1 GM095555) to J.W.; from the American Heart Association (12EIA8960018), March of Dimes Foundation (#6-FY11-260) and NIH (R01 HL118087 and RO1 HL121197) to C.-P.C.; from the NIH (R01 DC009410) to D.M.M.; and from the ACS, LLS and NIH (RO1 CA140875) to L.D.A.

Author information

Author notes

    • Colleen A. Brady
    • , Margaret M. Kozak
    •  & Thomas M. Johnson

    Present addresses: Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA (C.A.B.); Department of Medicine, University of Central Florida, Orlando, Florida 32827, USA (M.M.K.); Department of Emergency Medicine, Oregon Health and Science University, Portland, Oregon 97239, USA (T.M.J.).


  1. Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine, Stanford, California 94305, USA

    • Jeanine L. Van Nostrand
    • , Colleen A. Brady
    • , Heiyoun Jung
    • , Margaret M. Kozak
    • , Thomas M. Johnson
    •  & Laura D. Attardi
  2. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305, USA

    • Daniel R. Fuentes
    •  & Joanna Wysocka
  3. Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA

    • Chieh-Yu Lin
    •  & Hannes Vogel
  4. Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA

    • Chien-Jung Lin
    •  & Joanna Wysocka
  5. Department of Otolaryngology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Donald L. Swiderski
  6. Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305, USA

    • Jonathan A. Bernstein
  7. Département de Génétique, Hôpital Necker-Enfants Malades, APHP, 75015 Paris, France

    • Tania Attié-Bitach
  8. Unite INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France

    • Tania Attié-Bitach
  9. Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA

    • Ching-Pin Chang
  10. Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Donna M. Martin
  11. Department of Human Genetics, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA

    • Donna M. Martin
  12. Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA

    • Laura D. Attardi


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J.L.V.N. designed and carried out experiments, interpreted data and wrote the manuscript. C.A.B. generated the p5325,26,53,54 mice, designed and carried out experiments, and interpreted data. H.J. performed p53 ChIP analyses. M.M.K. and T.M.J. performed certain mouse analyses. D.R.F. and J.W. performed NCC differentiation and CHD7 ChIP analyses. C-Y.L., C-J.L. and C-P.C. assisted with heart analyses. D.L.S. and D.M.M. performed inner ear analyses, interpreted data and provided human fibroblasts. H.V. assisted with histological analyses. J.A.B. generated CHARGE and control human fibroblast lines. T.A.-B. performed TP53 sequencing analysis in patients and supplied CHARGE thymus samples. L.D.A. designed experiments, interpreted data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Laura D. Attardi.

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