Hypomorphic CEP290/NPHP6 mutations result in anosmia caused by the selective loss of G proteins in cilia of olfactory sensory neurons

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 40; pp. 15917 - 15922
• Main Authors: McEwen, Dyke P, Koenekoop, Robert K, Khanna, Hemant, Jenkins, Paul M, Lopez, Irma, Swaroop, Anand, Martens, Jeffrey R
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.10.2007; National Acad Sciences
• Subjects: Acetates; Alternative Splicing; Animals; Antibodies; Antigens, Neoplasm - genetics; Biological Sciences; Cilia; Disease Models, Animal; Female; Freight; Genetic Carrier Screening; Genetic mutation; Genetics; GTP-Binding Proteins - deficiency; Humans; Male; Mice; Mutation; Neoplasm Proteins - genetics; Neurons; Neurons, Afferent - pathology; Nose; Nuclear Proteins - genetics; Odorant receptors; Olfaction Disorders - genetics; Olfactory Mucosa - pathology; Olfactory Mucosa - physiology; Olfactory Pathways - pathology; Proteins; Retinal degeneration; Sensory neurons; Sensory perception; Sequence Deletion; Signal transduction; Smell; Smell - genetics; Smell - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0704140104

Cilia regulate diverse functions such as motility, fluid balance, and sensory perception. The cilia of olfactory sensory neurons (OSNs) compartmentalize the signaling proteins necessary for odor detection; however, little is known regarding the mechanisms of protein sorting/entry into olfactory cilia. Nephrocystins are a family of ciliary proteins likely involved in cargo sorting during transport from the basal body to the ciliary axoneme. In humans, loss-of-function of the cilia-centrosomal protein CEP290/NPHP6 is associated with Joubert and Meckel syndromes, whereas hypomorphic mutations result in Leber congenital amaurosis (LCA), a form of early-onset retinal dystrophy. Here, we report that CEP290-LCA patients exhibit severely abnormal olfactory function. In a mouse model with hypomorphic mutations in CEP290 [retinal dystrophy-16 mice (rd16)], electro-olfactogram recordings revealed an anosmic phenotype analogous to that of CEP290-LCA patients. Despite the loss of olfactory function, cilia of OSNs remained intact in the rd16 mice. As in wild type, CEP290 localized to dendritic knobs of rd16 OSNs, where it was in complex with ciliary transport proteins and the olfactory G proteins Golf and Gγ₁₃. Interestingly, we observed defective ciliary localization of Golf and Gγ₁₃ but not of G protein-coupled odorant receptors or other components of the odorant signaling pathway in the rd16 OSNs. Our data implicate distinct mechanisms for ciliary transport of olfactory signaling proteins, with CEP290 being a key mediator involved in G protein trafficking. The assessment of olfactory function can, therefore, serve as a useful diagnostic tool for genetic screening of certain syndromic ciliary diseases.