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.