Kisspeptin and Clinical Disorders - Kisspeptin Signaling in Reproductive Biology - page 190

cell surface after ligand-binding and signaling. Indeed, the p.R386P mutation
appears to decrease KISS1R degradation, resulting in a net increase of the receptor
on the plasma membrane [ 72 ].
Given the description of an activating mutation in KISS1R causing premature
activation of the gonadotropic axis, KISS1 was another obvious natural candidate
gene for precocious puberty. One rare kisspeptin variant, p.P74S, was identifi ed in
one child with sporadic CPP [ 70 ]. The p.P74S mutation was identifi ed in the hetero-
zygous state in a boy who developed CPP at 1 year of age with remarkably high
levels of basal LH and testosterone [ 70 ]. Although the majority of boys with CPP,
especially younger than 4 years old, have an underlying CNS abnormality [ 66 - 68 ],
this boy had no CNS lesions. His mother and maternal grandmother, who had nor-
mal pubertal development, also carried the p.P74S mutation in heterozygous state,
suggesting incomplete sex-dependent penetrance. After pre-incubating the mutant
kisspeptin in human serum to more closely mimic in vivo conditions, the capacity
to stimulate signal transduction was signifi cantly greater for p.P74S compared to
the wild type, suggesting that this variant might be more resistant to degradation,
resulting in greater kisspeptin bioavailability [ 70 ].
The patients with KISS1R or KISS1 mutations described above demonstrated ade-
quate response to conventional treatment with GnRH agonists [ 70 , 71 ]. Depot GnRH
agonist treatment resulted in the regression or stabilization of pubertal symptoms in
the two patients with activating mutations of KISS1R or KISS1 genes. As expected, a
decrease in the release of LH, FSH, and consequently normal pre-pubertal sexual
steroids was achieved in these cases. In addition, the discontinuation of depot GnRH
agonists treatment at the age higher than 11 years was associated with the reactiva-
tion of the reproductive axis in both cases, suggesting that the clinical and hormonal
features of patients with activating mutations of the KISS1R and KISS1 gene were not
different from children with idiopathic or organic causes of CPP.
Although these case reports expand the genotype-phenotype correlations for the
kisspeptin pathway, no other CPP cases with activating KISS1R or KISS1 mutations
have been reported, suggesting that these genetic abnormalities are very rare. Other
cohorts have been screened, but no mutations have been identifi ed in the KISS1 gene
[ 73 , 74 ]. Considering the low incidence of mutations in these genes in relation to the
frequency of familial CPP, it is possible that other genes involved in GnRH regula-
tion also will bear activating or inactivating mutations. Indeed, loss-of-function
mutations affecting repressor genes of the GnRH gene might play a role in the
pathogenesis of nonorganic CPP in the future.
Kisspeptin Expression in Organic Central Precocious Puberty
Hypothalamic hamartomas are the most common identifi able cause of CPP. Certain
characteristics of anatomy and neuropeptide expression have been proposed to be
associated with CPP. The expression of GnRH, GnRH receptor, TGFalpha, KISS1,
KISS1R, and GRM1A was investigated in hamartomas associated with or without