ClinVar

Dode et al. (2006) identified a 518T-G transversion in exon 2 of the PROKR2 gene, resulting in a leu173-to-arg (L173R) substitution, in patients with Kallmann syndrome (HH3; 244200). The mutation was found in heterozygous state in a family and in 3 sporadic cases, in homozygous state in a sporadic case, and in compound heterozygous state with a Q210R mutation (607123.0002) in another family. In a sporadic case of Kallmann syndrome, Dode et al. (2006) found heterozygosity for L173R as well as heterozygosity for a mutation in the KAL1 gene (300836.0012), suggesting digenic inheritance. The L173R and Q210R mutations in the PROKR2 gene were not found in 500 ethnically matched (Caucasian) control alleles.

In 2 unrelated male patients with Kallmann syndrome, Cole et al. (2008) identified heterozygosity for the L173R 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 L173R mutant compared to wildtype in both assays. Both patients had complete absence of puberty with undetectable levels of luteinizing hormone (LH; 152780), and their sense of smell was below the fifth percentile on olfactory testing; MRI performed in 1 of the patients showed absence of the olfactory bulbs. Additional features included pes planus, pectus excavatum, and synkinesia in 1 patient and cryptorchidism in the other.

Monnier et al. (2009) performed functional analysis of the L173R mutation in HEK293 cells and demonstrated decreased signaling and impaired cell-surface targeting of the receptor compared to wildtype.