Molecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations - Kisspeptin Signaling in Reproductive Biology - page 146

incidence of CPP, most of the mutations affecting fertility have been identifi ed in
patients with IHH. This could suggest that idiopathic CPP would be a polygenic
disorder; however, the autosomal-dominant transmission observed in families with
a history of idiopathic CPP disagrees with a polygenic origin for this disorder. The
fi rst report of a naturally occurring genetic mutation associated with CPP was pub-
lished quite recently. This mutation is a single amino acid substitution in the car-
boxyl terminal tail of KISS1R (Arg386Pro) identifi ed in an affected girl [ 6 ]. One
additional single amino acid substitution in the KISS1R ligand, kisspeptin, has also
been associated with the CPP phenotype in an unrelated boy [ 17 ]. Both mutations
have had their association with the CPP phenotype confi rmed in functional assays
and were identifi ed in the heterozygous state in the affected children, consistent
with the autosomal-dominant inheritance mode of CPP predicted in familial cases
of the disorder.
The Arg386Pro-KISS1R, the First Mutation
to be Associated with CPP
The Arg386Pro-KISS1R mutation was identifi ed in a girl who exhibited slowly
progressing thelarche since birth [ 6 ]. At age 8.5 years, the affected girl had advanced
breast development and pubic hair as well as additional signs of precocious expo-
sure to estrogen, such as enlarged uterine and ovarian volumes and a 3-year advanced
bone age for her chronological age. Accordingly, her serum estradiol was twice the
value expected for her age [ 6 ]. Despite the elevated estradiol, her basal and stimu-
lated LH responses were within the expected range for her age, suggesting that the
underlying defect led to stimulation of the central reproductive axis.
Arginine at position 386 is a conserved amino acid in an otherwise poorly con-
served domain of the KISS1R, which suggests that this amino acid is relevant for
receptor function. Accordingly, functional assays showed that this mutation resulted
in prolonged responsiveness of the mutant receptor to kisspeptin stimulation, as
indicated by inositol phosphate production and phosphorylation of ERK1/2, which
were used as markers of KISS1R-activated G protein signaling in cells transfected
with the Arg386Pro mutant or the wild-type KISS1R [ 6 ].
Basal KISS1R activity (i.e., activity in the absence of agonist stimulation) was
not affected by the Arg386Pro mutation. This important detail indicates that, unlike
the well-established effects of naturally occurring genetic mutations identifi ed in
patients with gonadotropin-independent precocious puberty, the Arg386Pro KISS1R
mutation does not generate a constitutively active receptor [ 6 ]. Instead, the
Arg386Pro mutation was associated with a mild gain-of-function effect that was
only detected after prolonged stimulation with kisspeptin. This observation points
to a slower rate of desensitization of the Arg386Pro KISS1R mutant, consistent with
a mutation in the carboxyl terminal tail—a well-known target of intracellular