ClinVar

In a patient with sporadic Kallmann syndrome (HH3; 244200), Dode et al. (2006) identified heterozygosity for a c.533G-C transversion in exon 2 of the PROKR2 gene, resulting in a trp178-to-ser (W178S) substitution in the T4 domain. The mutation was not found in 500 ethnically matched (Caucasian) alleles.

In a male patient with normosmic hypogonadotropic hypogonadism, Cole et al. (2008) identified heterozygosity for the W178S mutation in the PROKR2 gene. The mutation was not found in 346 control alleles. Functional analysis involving gene transcription and calcium flux assays demonstrated severely compromised activity with the W178S mutant compared to wildtype in both assays. The patient did not undergo puberty and had a normal sense of smell on olfactory testing. He exhibited a pulsatile pattern of luteinizing hormone (LH; see 152780) and had elevated LH and follicle-stimulating hormone (FSH; see 136435) levels in the setting of hypogonadal testosterone levels. Cole et al. (2008) noted that the LH secretion pattern was hypergonadotropic, although not in the range of males with primary gonadal failure, suggesting a dual hypothalamic and gonadal defect that involved insufficient GNRH (152760) secretion as well as primary gonadal resistance.

Monnier et al. (2009) performed functional analysis of the W178S mutation in HEK293 cells and observed impaired cell-surface targeting of the receptor with the W178S mutant compared to wildtype.