Molecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations - Kisspeptin Signaling in Reproductive Biology - page 149

precocious puberty, as the expression of a constitutively active KISS1R would lead
to permanent desensitization of KISS1R signaling, regardless of the presence of
kisspeptin.
Further support for the prediction that mild gain-of-function is key for the mani-
festation of a precocious puberty phenotype came from the functional characteriza-
tion of another naturally occurring mutation associated with idiopathic CPP in a
boy. The mutation in this boy is in kisspeptin (Pro74Ser) [ 25 ]. Similarly to the
Arg386Pro-KISS1R, the Pro74Ser kisspeptin mutant also results in a relatively mild
gain-of-function characterized by prolonged KISS1R signaling. Functional assays
indicated that the Pro74Ser kisspeptin mutant was degraded more slowly than the
wild type kisspeptin [ 25 ]. Thus, the mild gain-of-function effects of both the
Arg386Pro KISS1R and the Pro74Ser kisspeptin mutations lead to prolonged kiss-
peptin signaling, which contributes to the precocious puberty phenotype in the
patients carrying these mutations.
Final Considerations
Additional mutations in KISS1R or KISS1 not yet characterized in functional assays
have been identifi ed in a screen for polymorphisms in Chinese girls with CPP. A
Pro196His KISS1R mutation that is located in the second extracellular loop of the
receptor and a Pro110 Thr kisspeptin mutant were identifi ed in these studies [ 26 ,
27 ]. Whether these mutations are associated with the precocious puberty phenotype
in the affected girls has not been established.
The characterization of mutations in KISS1R or KISS1 , as well as the disruption
of the genes encoding KISS1R or kisspeptin, have established the relevance of
KISS1R signaling for triggering pubertal maturation and maintaining reproductive
competence in humans and animal models. Further characterization has revealed a
role for the duration of KISS1R signaling in the onset and timing of pubertal matura-
tion. These fi ndings underscore the importance of identifi cation of additional intra-
cellular pathways or networks controlling KISS1R signaling, as mutations in proteins
potentially involved in these networks and signaling pathways may be responsible
for additional yet-unidentifi ed cases of pubertal and reproductive disorders.
In addition, investigation of the effect of loss- and gain-of-function mutations in
KISS1R in sites outside of the hypothalamus where the expression of this receptor
may contribute to overall reproductive function and/or fertility may help to uncover
new functions for the KISS1R.
Acknowledgments This work was supported by the Eunice Kennedy Shriver National Institute of
Child Health and Human Development, National Institutes of Health (NIH), through cooperative
agreement U54 HD28138 as part of the Specialized Cooperative Centers Program in Reproduction
and Infertility Research, by R01 HD61577, and by R21 HD66495 (to UBK) as well as by the R21
HD059015 and ARRA R21 HD059015-02S1 (SDCB) and by the 2008 Child Health Research
Award from the Charles H. Hood Foundation, Boston, MA (SDCB).