title: Mutations in olfactory signal transduction genes are not a major cause of human congenital general anosmia.
abstract: Anosmia affects the western world population, mostly the elderly, reaching to 5% in subjects over the age of 45 years and strongly lowering their quality of life. A smaller minority (about 0.01%) is born without a sense of smell, afflicted with congenital general anosmia (CGA). No causative genes for human CGA have been identified yet, except for some syndromic cases such as Kallman syndrome. In mice, however, deletion of any of the 3 main olfactory transduction components (guanidine triphosphate binding protein, adenylyl cyclase, and the cyclic adenosine monophosphate-gated channel) causes profound reduction of physiological responses to odorants. In an attempt to identify human CGA-related mutations, we performed whole-genome linkage analysis in affected families, but no significant linkage signals were observed, probably due to the small size of families analyzed. We further carried out direct mutation screening in the 3 main olfactory transduction genes in 64 unrelated anosmic individuals. No potentially causative mutations were identified, indicating that transduction gene variations underlie human CGA rarely and that mutations in other genes have to be identified. The screened genes were found to be under purifying selection, suggesting that they play a crucial functional role not only in olfaction but also potentially in additional pathways.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ester
authors.initials: E
authors.lastname: Feldmesser
authors.forename: Dani
authors.initials: D
authors.lastname: Bercovich
authors.forename: Nili
authors.initials: N
authors.lastname: Avidan
authors.forename: Shmuel
authors.initials: S
authors.lastname: Halbertal
authors.forename: Liora
authors.initials: L
authors.lastname: Haim
authors.forename: Ruth
authors.initials: R
authors.lastname: Gross-Isseroff
authors.forename: Sivan
authors.initials: S
authors.lastname: Goshen
authors.forename: Doron
authors.initials: D
authors.lastname: Lancet
mesh_terms: D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D054815:Cyclic Nucleotide-Gated Cation Channels; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D008040:Genetic Linkage; D006801:Humans; D007473:Ion Channels / Q000235:genetics; D008297:Male; D009154:Mutation; D000857:Olfaction Disorders / Q000151:congenital* / Q000235:genetics; D010375:Pedigree; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D044385:GTP-Binding Protein alpha Subunits; D007473:Ion Channels; C084618:olfactory G protein subunit alpha olf