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occurring loss-of-function (or inactivating) mutations in
KISS1R
, who present
with IHH [
8
-
11
,
13
-
15
], a syndrome characterized by lack of sexual maturation
and infertility associated with low levels of circulating gonadotropins and sex
steroids [
2
]. This is further supported by a similar IHH phenotype exhibited by
mice lacking Kiss1r [
21
-
23
,
36
] or kisspeptin [
20
,
23
] expression. Interestingly,
mice lacking Kiss1r expression exhibit a reproductive phenotype that is more
severe than that of mice lacking kisspeptin. This raises the potential for addi-
tional yet-unknown endogenous ligands for Kiss1r other than those expressed by
the
Kiss1
gene. However, failed attempts to identify other endogenous ligands
[
37
,
38
], as well as the severity of the phenotype of kisspeptin null mice [
20
,
23
],
do not support the existence of additional endogenous ligands for Kiss1r. Another
possibility would be ligand-independent signaling by the Kiss1r, which is sup-
ported by studies showing constitutive activity (in the absence of ligand) of
KISS1R in transfected cells [
39
,
40
]. Regardless, the basis for the more severe
phenotype in Kiss1r null mice remains to be established. Nonetheless, it is simi-
lar to the more severe phenotype exhibited in other mouse models of receptor
disruption when compared to that resulting from the disruption of the cognate
ligands.
Conversely, the fi rst genetic mutation to be associated with idiopathic
gonadotropin-dependent (or central) precocious puberty (CPP), a syndrome charac-
terized by the unexplained premature activation of the hypothalamic-pituitary-
gonadal (or reproductive) axis, was a single amino acid substitution in KISS1R
(Arg386Pro-KISS1R) identifi ed in an affected girl [
6
]. Functional characterization
indicates that the Arg386Pro substitution impairs KISS1R degradation, which
results in gain-of-function [
6
,
41
].
These opposing phenotypes of patients carrying loss- or gain-of-function muta-
tions in
KISS1R
emphasize the critical role of KISS1R signaling for normal repro-
ductive maturation and function, and highlight the potential disease risks of
abnormal KISS1R function. In order to prevent abnormal KISS1R activity or func-
tion and its associated risks, it is important to understand the precise mechanisms
involved. Recent advances in this area include studies of KISS1R intracellular traf-
fi cking and binding partners, as well as the use of naturally occurring human muta-
tions, in order to understand the mechanisms by which these mutations affect
receptor function. The confi rmed or predicted molecular mechanisms underlying
loss- or gain-of-function effects of reported KISS1R mutations associated with
pubertal disorders will be discussed below.
KISS1R Signaling Pathway
The gene encoding KISS1R was initially named
GPR54
for being the 54th orphan
GPCR identifi ed by sequence homology [
42
], but is now typically referred to as
KISS1R
[
43
]. GPCRs are plasma membrane receptors that share a seven transmem-
brane spanning domain organization in which the amino-terminus is extracellular
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