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expression [ 21 , 36 ]. Male mice from this lineage are reported to lack male mounting
behavior, which can be rescued by adulthood testosterone supplementation [ 36 ].
Normal copulatory behavior was also restored in adult females supplemented with
estrogen [ 36 ]. On the other hand, other abnormalities exhibited by Kiss1r null males
could not be rescued by testosterone supplementation, such as the absence of the
normal female preference when mounting, the female-like (low) number of moto-
neurons in the spino-bulbocavernosus nucleus, as well as female-like tyrosine
hydroxylase fi bers and kisspeptin expression in the AVPV, which suggests that
some of the abnormalities caused by disruption of Kiss1r gene may be permanent
once established [ 36 ].
As opposed to female mice from all other lineages carrying Kiss1r gene dele-
tions, Kiss1r null females from the viral targeting lineage were reported to respond
to sex steroid treatment with activation of GnRH neurons (as indicated by cFos
induction), as well as a signifi cant increase in serum LH [ 21 ]. Similar experiments
failed to reproduce these results in females from the Paradigm Therapeutics lin-
eage, which showed no cFos activation in GnRH neurons, and none of the Kiss1r
null females exhibited an LH response to the sex steroid regimens [ 70 ]. Incidentally,
females that responded to the sex steroid regimen belong to the only lineage of
Kiss1r gene disruption without any deletions in the coding sequence. Although in
situ hybridization did not detect signifi cant Kiss1r expression in mice from this
lineage, residual gene expression in cases of retroviral insertions has been reported,
which could be achieved by splicing out the inserted gene from the RNA [ 69 ].
Gain-of-Function of Kiss1r and Central Precocious Puberty
Gonadotropin-dependent or CPP is characterized by advanced sexual maturation
that is originated at the central nervous system level. These cases are further classi-
fi ed as idiopathic after tumors or other anatomical abnormalities have been excluded
[ 71 ]. The etiology in idiopathic cases is thought to relate primarily to genetic fac-
tors, with additional infl uences of environmental and dietary factors [ 72 - 76 ].
Prevalence of CPP is substantially higher than that of IHH in any given popula-
tion, and girls are at least ten times more likely to develop CPP than boys [ 74 , 76 -
78 ]. This likelihood is further increased when only idiopathic cases of the disorder
are considered [ 79 , 80 ]. The genetic nature of this disorder is emphasized by the fact
that about a third of affected children have a family history of the disorder [ 77 ].
Moreover, at least 95% of girls with CPP have the idiopathic form of the disorder
[ 71 ]. On the other hand, the majority of CPP cases in boys are a consequence of
anatomical defects [ 71 ]. These differences reveal a sexually dimorphic pattern of
incidence of pubertal disorders in children.
The analysis of families with a history of idiopathic CPP suggests an autosomal-
dominant inheritance mode of this disorder [ 77 ]. Thus, one mutant allele would be
suffi cient to result in the manisfestation of the CPP phenotype. Despite the higher
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