Kisspeptin and Clinical Disorders - Kisspeptin Signaling in Reproductive Biology - page 185

p.R331X or p.X399R transcripts, in vitro studies suggested that each of the mutant
proteins would have functioned poorly.
Understanding the functional consequences of the p.R331X/p.X399R mutations
was an important backdrop for the interpretation of the clinical presentation of the
p.R331X/p.X399R proband [ 4 ]. On frequent blood sampling, this individual had
low-amplitude pulses of luteinizing hormone (LH), suggesting present, but enfee-
bled, secretion of GnRH. He also had a left-shifted dose-response curve compared
to other patients with GnRH defi ciency undergoing the same therapy, suggesting
that he may be more sensitive to exogenous GnRH. Thus, despite the clear impor-
tance of the kisspeptin pathway in modulating GnRH release, the clinical data from
this patient suggested the possibility of residual GnRH activity, a foreshadowing of
subsequent studies that were performed in the rodent demonstrating the existence of
kisspeptin-independent GnRH secretion [ 8 ].
The clinical presentations of the p.L148S and p.R331X/p.X399R patients were
also juxtaposed against the phenotype of Kiss1r- defi cient mice; the mutant mice were
striking phenocopies of the GnRH-defi cient patients, including lack of sexual matu-
ration associated with low levels of gonadotropins [ 4 ]. The strong parallels in presen-
tation between the GnRH-defi cient patients and the mutant mice established a central
role for KISS1R / Kiss1r across mammalian species. Moreover, the use of a mouse
model allowed quantifi cation of hypothalamic GnRH content, which was found to be
normal in the Kiss1r- defi cient mice, suggesting that KISS1R / Kiss1r infl uences the
timing of sexual maturation by affecting the processing or secretion of GnRH [ 4 , 9 ].
Thus, the identifi cation of mutations in KISS1R by multiple groups thrust the
kisspeptin pathway into the spotlight, and laboratories around the world began
assembling expression, physiologic, transgenic, knock out/down, and electrophysi-
ologic data to tell the biologic story of kisspeptin and its important role in regulating
GnRH secretion. The hypothesis that kisspeptin does not affect GnRH neuronal
migration, but rather GnRH biosynthesis and/or release, was supported shortly
thereafter by in vivo studies demonstrating that kisspeptin administration, either
centrally or peripherally, triggers robust GnRH-induced LH and FSH secretion [ 10 ,
11 ]. Kisspeptin expression in the hypothalamus of rodents and nonhuman primates
was also found to increase at the time of sexual maturation [ 11 , 12 ], an important
fi nding since kisspeptin is thought to mediate sex steroid feedback [ 12 - 17 ], estrous
cycle regulation [ 17 , 18 ], seasonal breeding [ 19 - 25 ], and to convey information
about the energy status of the organism [ 26 , 27 ]. Thus, relatively quickly, kisspeptin
was found to be a key gatekeeper for the activation of the GnRH axis.
Central Themes for Patients Carrying Mutations
in the Kisspeptin Signaling Pathway
Once KISS1R was added to the roster of genes for GnRH defi ciency, several groups
began to search for mutations in the kisspeptin signaling pathway in patients with
hypogonadotropic hypogonadism. However, mutations in the coding sequence of
KISS1R have proven to be relatively rare, particularly in comparison with many other