Molecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations - Kisspeptin Signaling in Reproductive Biology - page 130

Introduction
The initiation of puberty onset is fi rst detected as an increase in frequency and
amplitude of gonadotropin-releasing hormone (GnRH) pulses by the hypothalamus,
which is followed by increased secretion of the gonadotropins, luteinizing hormone
(LH) and follicle-stimulating hormone (FSH), by the pituitary gland [ 1 ]. Failure to
increase GnRH or gonadotropin secretion during puberty is the underlying cause of
idiopathic hypogonadotropic hypogonadism (IHH) [ 2 ]. Conversely, premature acti-
vation of GnRH pulsatility leads to idiopathic gonadotropin-dependent (or central)
precocious puberty (ICPP). The upstream mechanisms driving the hallmark increase
in GnRH pulsatility during puberty, however, are not well defi ned. Insights into
these mechanisms have been provided by the identifi cation and characterization of
mutations associated with reproductive disorders in affected patients [ 3 - 7 ]. As a
result of these studies, an increasing array of genes has been implicated in the con-
trol of pulsatile GnRH secretion and in the etiology of central reproductive disor-
ders. The involvement of kisspeptin and its cognate G protein-coupled receptor
(GPCR), kisspeptin receptor (KISS1R), in puberty and reproductive function was
not recognized until 2003, when two independent groups identifi ed loss-of-function
mutations in KISS1R in unrelated patients with a family history of IHH and normal
sense of smell (normosmic IHH or nIHH) [ 8 , 9 ]. Reports of additional loss-of-
function mutations in KISS1R or its ligand in association with nIHH in affected
patients have followed [ 10 - 19 ]. Moreover, targeted disruption of the Kiss1r , or of
the Kiss1 gene encoding the ligand, results in a similar phenotype of hypogonado-
tropic hypogonadism and infertility in mice [ 9 , 20 - 23 ], with Kiss1r null mice dis-
playing a more severe phenotype than Kiss1 null mice [ 24 ]. Nevertheless, mutations
in Kiss1r are predicted to account for a small percentage (~5%) of the total human
cases of nIHH [ 7 ]. This percentage reaches about 20% if only familial cases of nor-
mosmic IHH are considered [ 7 ].
Five years after the publication of the fi rst cases of KISS1R mutants associated
with IHH, the critical role of KISS1R on pubertal development was further rein-
forced when a single amino acid substitution in KISS1R in a girl with CPP was
identifi ed. This amino acid substitution was the fi rst genetic mutation reported to be
associated with CPP [ 6 ]. Two years later, a second mutation was identifi ed in a boy
with CPP, this time in the KISS1R ligand, kisspeptin [ 25 ]. An additional mutation
in kisspeptin was identifi ed in the heterozygous state in two unrelated Brazilian girls
with CPP; however, in vitro analyses fail to identify associated alterations in kiss-
peptin function or activity [ 25 ]. Genome-wide association studies have shown sig-
nifi cant association of two polymorphisms—one in KISS1 and the other in
KISS1R —with CPP in a Chinese population [ 26 , 27 ]; however, no functional assays
have been performed.
To date, kisspeptin/KISS1R is the only ligand/receptor system with confi rmed
association of identifi ed mutations with both IHH and precocious puberty pheno-
types in affected patients, which underscores the role of this ligand/receptor pair in
the onset of puberty. This chapter will discuss details of KISS1R traffi cking and