Mutations in Olfactory Signal Transduction Genes Are Not a Major Cause of Human Congenital General Anosmia

Feldmesser, Ester; Bercovich, Dani; Avidan, Nili; Halbertal, Shmuel; Haim, Liora; Gross‐Isseroff, Ruth; Goshen, Sivan; Lancet, Doron

doi:10.1093/chemse/bjl032

Cited by 35 publications

(55 citation statements)

References 71 publications

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“…ICA may be due to developmental abnormalities such as olfactory bulb agenesis. It may also occur in the absence of developmental defect, possibly as a result of deficient intracellular signaling in the olfactory receptor pathway (2,3,4).…”

Section: Introductionmentioning

confidence: 99%

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PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency

Moya‐Plana

Villanueva

Laccourreye

et al. 2013

European Journal of Endocrinology

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Objective: Isolated congenital anosmia (ICA) is a rare phenotype defined as absent recall of any olfactory sensations since birth and the absence of any disease known to cause anosmia. Although most cases of ICA are sporadic, reports of familial cases suggest a genetic cause. ICA due to olfactory bulb agenesis and associated to hypogonadotropic hypogonadism defines Kallmann syndrome (KS), in which several gene defects have been described. In KS families, the phenotype may be restricted to ICA. We therefore hypothesized that mutations in KS genes cause ICA in patients, even in the absence of family history of reproduction disorders. Design and methods: In 25 patients with ICA and olfactory bulb agenesis, a detailed phenotype analysis was conducted and the coding sequences of KAL1, FGFR1, FGF8, PROKR2, and PROK2 were sequenced. Results: Three PROKR2 mutations previously described in KS and one new PROK2 mutation were found. Investigation of the families showed incomplete penetrance of these mutations. Conclusions: This study is the first to report genetic causes of ICA and indicates that KS genes must be screened in patients with ICA. It also confirms the considerable complexity of GNRH neuron development in humans.

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Section: Introductionmentioning

confidence: 99%

“…Most ICA cases are sporadic, but familial cases with dominant and reduced penetrance have been reported (3,4). The mode of transmission of syndromic CA is mainly determined by that of the underlying syndrome.…”

Section: Introductionmentioning

confidence: 99%

PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency

Moya‐Plana

Villanueva

Laccourreye

et al. 2013

European Journal of Endocrinology

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“…Since Glaser et al . first reported ICA as a potentially hereditary trait nearly 100 years ago 10 , there have been few candidate genes identified as the potential genetic cause for ICA 3, 6, 11–13 . Moreover, most reported anosmia cases are inherited through autosomal dominant patterns 2, 14 , however, in some instances, it is an X-linked trait 3, 6, 10 .…”

Section: Introductionmentioning

confidence: 99%

Isolated Congenital Anosmia and CNGA2 Mutation

Sailani

Inlora

MirMazlomi³

et al. 2017

Sci Rep

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Isolated congenital anosmia (ICA) is a rare condition that is associated with life-long inability to smell. Here we report a genetic characterization of a large Iranian family segregating ICA. Whole exome sequencing in five affected family members and five healthy members revealed a stop gain mutation in CNGA2 (OMIM 300338) (chrX:150,911,102; CNGA2. c.577C > T; p.Arg193*). The mutation segregates in an X-linked pattern, as all the affected family members are hemizygotes, whereas healthy family members are either heterozygote or homozygote for the reference allele. cnga2 knockout mice are congenitally anosmic and have abnormal olfactory system physiology, additionally Karstensen et al. recently reported two anosmic brothers sharing a CNGA2 truncating variant. Our study in concert with these findings provides strong support for role of CNGA2 gene with pathogenicity of ICA in humans. Together, these results indicate that mutations in key olfactory signaling pathway genes are responsible for human disease.

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“…However, no genetic factors had been defined for Type II congenital smell loss despite earlier attempts [8]. In an effort to explore a genetic abnormality present in patients with Type II congenital smell loss, we performed extensive erythrocyte surface antigen testing among these patients [9].…”

Section: Introductionmentioning

confidence: 99%

A genetic marker of the ACKR1 gene is present in patients with Type II congenital smell loss who have type I hyposmia and hypogeusia

Stateman

Knöppel

Flegel

et al. 2016

American Journal of Otolaryngology

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PURPOSE Our previous study of Type II congenital smell loss patients revealed a statistically significant lower prevalence of an FY (ACKR1, formerly DARC) haplotype compared to controls. The present study correlates this genetic feature with subgroups of patients defined by specific smell and taste functions. METHODS Smell and taste function measurements were performed by use of olfactometry and gustometry to define degree of abnormality of smell and taste function. Smell loss was classified as anosmia or hyposmia (types I, II or III). Taste loss was similarly classified as ageusia or hypogeusia (types I, II or III). Based upon these results patient erythrocyte antigen expression frequencies were categorized by smell and taste loss with results compared between patients within the Type II group and published controls. RESULTS Comparison of antigen expression frequencies revealed a statistically significant decrease in incidence of an Fyb haplotype only among patients with type I hyposmia and any form of taste loss (hypogeusia). In all other patient groups erythrocyte antigens were expressed at normal frequencies. CONCLUSIONS Data suggest that Type II congenital smell loss patients who exhibit both type I hyposmia and hypogeusia are genetically distinct from all other patients with Type II congenital smell loss. This distinction is based on decreased Fyb expression which correlated with abnormalities in two sensory modalities (hyposmia type I and hypogeusia). Only patients with these two specific sensory abnormalities expressed the Fyb antigen (encoded by the ACKR1 gene on the long arm of chromosome 1) at frequencies different from controls.

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Mutations in Olfactory Signal Transduction Genes Are Not a Major Cause of Human Congenital General Anosmia

Cited by 35 publications

References 71 publications

PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency

PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency

Isolated Congenital Anosmia and CNGA2 Mutation

A genetic marker of the ACKR1 gene is present in patients with Type II congenital smell loss who have type I hyposmia and hypogeusia

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