PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency

Abstract

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.

The first mutation in CNGA2 in two brothers with anosmia

“…Next, exome sequencing of I-1 and I-2 was carried out using the Nextera Rapid Capture Expanded Exome kit (Illumina, San Diego, CA). Previously, mutations in known Kallmann syndrome genes have been identified in an ICA cohort (13). The average read depth was 81 reads in both samples with 85-88% of the targeted region being covered at least 20-fold.…”

“…Whereas, the genetic etiology has been described for a list of syndromes, where anosmia is part of the clinical picture, no human mutations have been ascribed to ICA outside the list of genes identified in syndromic anosmia. 607002) have been described in a cohort suffering from ICA (13). 603415), where patients present with congenital insensitivity to pain together with anosmia (11).…”

MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism

“…in those with a history of cryptorchidism and/or micropenis at birth (29,49,51). Moreover, some reversal patients lack olfactory structures (44,52) pointing to the possibility that recovery of GnRH neuronal function may not always be dependent on intact olfactory structures (53). Interestingly, hypothalamic progenitor cells in rat can give rise to GnRH neurons, suggesting that postnatal genesis of GnRH neurons can occur in certain circumstances (54).…”

Isolated Congenital Anosmia and CNGA2 Mutation

“…Rarely, however, it can occur as a congenital condition (prevalence 1 in 10,000) 21 (Isolated Congenital Anosmia) (Online Mendelian Inheritance in Man [OMIM] % 107200). Few candidate genes have been identified as potential causal genes for ICA in humans 3, 6, 11–13, 22 . For instance, Karstensen et al .…”

“…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 .…”