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Defects in neural stem cell proliferation and olfaction in Chd7 deficient mice indicate a mechanism for hyposmia in human CHARGE syndrome.

Mutations in CHD7, a chromodomain gene, are present in a majority of individuals with CHARGE syndrome, a multiple anomaly disorder characterized by ocular Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital hypoplasia and Ear anomalies. The clinical features of CHARGE syndrome are highly variable and incompletely penetrant. Olfactory dysfunction is a common feature in CHARGE syndrome and has been potentially linked to primary olfactory bulb defects, but no data confirming this mechanistic link have been reported. On the basis of these observations, we hypothesized that loss of Chd7 disrupts mammalian olfactory tissue development and function. We found severe defects in olfaction in individuals with CHD7 mutations and CHARGE, and loss of odor evoked electro-olfactogram responses in Chd7 deficient mice, suggesting reduced olfaction is due to a dysfunctional olfactory epithelium. Chd7 expression was high in basal olfactory epithelial neural stem cells and down-regulated in mature olfactory sensory neurons. We observed smaller olfactory bulbs, reduced olfactory sensory neurons, and disorganized epithelial ultrastructure in Chd7 mutant mice, despite apparently normal functional cilia and sustentacular cells. Significant reductions in the proliferation of neural stem cells and regeneration of olfactory sensory neurons in the mature Chd7(Gt/+) olfactory epithelium indicate critical roles for Chd7 in regulating neurogenesis. These studies provide evidence that mammalian olfactory dysfunction due to Chd7 haploinsufficiency is linked to primary defects in olfactory neural stem cell proliferation and may influence olfactory bulb development.

Pubmed ID: 19279158


  • Layman WS
  • McEwen DP
  • Beyer LA
  • Lalani SR
  • Fernbach SD
  • Oh E
  • Swaroop A
  • Hegg CC
  • Raphael Y
  • Martens JR
  • Martin DM


Human molecular genetics

Publication Data

June 1, 2009

Associated Grants

  • Agency: NIDCD NIH HHS, Id: R01 DC006897
  • Agency: NIDCD NIH HHS, Id: R01 DC006897-06
  • Agency: NIDCD NIH HHS, Id: R01 DC009410
  • Agency: NIDCD NIH HHS, Id: R01 DC009410
  • Agency: NIDCD NIH HHS, Id: R01 DC009606
  • Agency: NINDS NIH HHS, Id: R01 NS054784
  • Agency: NIDCD NIH HHS, Id: T32 DC00011

Mesh Terms

  • Abnormalities, Multiple
  • Animals
  • Cell Proliferation
  • Child
  • DNA Helicases
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Mutation
  • Olfaction Disorders
  • Olfactory Mucosa
  • Sensory Receptor Cells
  • Smell
  • Stem Cells