Kisspeptin and Clinical Disorders - Kisspeptin Signaling in Reproductive Biology - page 189

and Kiss1r −/− female mice, demonstrating that this estrus is due to GnRH activity.
The low-amplitude LH pulsations observed in multiple patients with KISS1R muta-
tions appears to be echoed in the persistent GnRH activity documented in Kiss1 −/−
and Kiss1r −/− mice. Kisspeptin-independent GnRH activity, whether in mice or men,
could be due to low level constitutive activity of GnRH neurons or could be induced
by other neuroendocrine pathways that modulate GnRH neuronal secretion.
Surprisingly, mice with targeted ablation of kisspeptin or kisspeptin receptor
expressing cells (as opposed to deletion of the Kiss1 and Kiss1r genes ) are almost
entirely reproductively normal suggesting, at initial interpretation, that kisspeptin
signaling is not required for puberty and fertility [ 60 ]. However, the residual kiss-
peptin and GnRH neurons present in each of these cellular ablation mouse models,
while quite small in number, may in fact be suffi cient for sexual maturation and
fertility, as initially suggested by preoptic area brain grafts in hypogonadal ( hpg )
mice [ 61 , 62 ] and a more recent mouse model ( Kiss Cre / Cre ) with markedly reduced
expression of Kiss1 [ 63 ].
From Loss-of-Function to Gain-of-Function
in the Kisspeptin Signaling Pathway
While GnRH defi ciency presents with delayed pubertal development, central preco-
cious puberty (CPP) results from early activation of hypothalamic GnRH secreting
neurons resulting in precocious pubertal development in childhood [ 64 , 65 ].
Affected children present with premature development of secondary sexual charac-
teristics, acceleration of linear growth, and progressive skeletal maturation, result-
ing in premature epiphyseal closure and, consequently, short adult height in untreated
cases [ 66 ]. CPP has remarkable female gender predominance and most cases are
considered idiopathic, with normal central nervous system (CNS) magnetic reso-
nance imaging (MRI) [ 64 - 68 ]. However, up to 75% of boys with CPP have a detect-
able CNS lesion, mainly hypothalamic hamartomas [ 64 - 67 ]. Familial occurrence
has been reported in 20-25% of CPP cases, suggesting a role for genetic factors in
its pathogenesis [ 69 , 70 ]. Segregation analysis of these families suggested an auto-
somal dominant transmission with incomplete sex-dependent penetrance [ 69 ].
In 2008, the kisspeptin signaling pathway was implicated in the pathogenesis of
CPP. The fi rst heterozygous activating mutation of the KISS1R (p.R386P) was
described in an adopted Brazilian girl with CPP [ 71 ]. She presented with slowly
progressive thelarche from birth; accelerated growth, skeletal maturation, and pro-
gression of breast development were noticed at 7 years of age. She had pubertal
estradiol levels and borderline-pubertal LH stimulated levels [ 71 ]. In vitro studies
demonstrated that the R386P mutation, located in the carboxy terminal tail of the
receptor, led to prolonged activation of intracellular signaling pathways in response
to kisspeptin [ 71 ]. Therefore, in contrast to gain-of-function mutations in many G
protein-coupled receptors, which cause constitutive receptor activation, the p.R386P
mutation appeared to reduce the rate of desensitization of the mutant KISS1R at the