Kisspeptin and Clinical Disorders - Kisspeptin Signaling in Reproductive Biology - page 188

The Missing Link of KISS1

In GnRH defi ciency, the discovery of loss-of-function mutations in genes encoding
cell membrane-associated receptors has always preceded or accompanied the dis-
covery of disabling mutations in the genes encoding their ligands. Initially, it
appeared that KISS1 was going to escape this genetic tradition, as no mutations in
KISS1 were reported for 8 years after the discovery of mutations in KISS1R .
However, mutations in KISS1 are now clearly associated with GnRH defi ciency.
In 2011, 15 probands with GnRH defi ciency were found to harbor 10 heterozy-
gous rare sequence variants in KISS1 [ 56 ]; in silico, in vitro, and in vivo studies
were performed to explore the functional consequences of these variants. p.F117L
was found to reduce inositol phosphate generation in vitro. p.G35S and p.C53R
were predicted in silico to be deleterious. Lying outside the coding region, the vari-
ant g.1-3659C

→ T was found to impair transcription in vitro while another variant,

c.1-7C T, was noted to sit within the consensus Kozak sequence. Because these

variants were monoallelic, and not biallelic, an examination of reproductive pheno-
types in heterozygous and double-heterozygous Kiss1 and Kiss1r mice was also
performed. Heterozygous Kiss1 mutations produced reproductive phenotypes in
mutant mice and these phenotypes were further accentuated when accompanied by
heterozygous mutations in Kiss1r [ 56 ].
As over 1,000 probands were screened to identify these nucleotide changes, dis-
abling genetic variation in KISS1 is clearly as rare, if not more so, than that of
KISS1R . However, a homozygous loss-of-function mutation in KISS1 was eventu-
ally discovered in affected siblings from a consanguineous Kurdish pedigree with
normosmic GnRH defi ciency (c.345C

→

G; p.N115K) [ 57 ]. The mutant kisspeptin
was signifi cantly less potent than wild type kisspeptin in activating GnRH neurons.
Thus, both KISS1R and KISS1 are clearly genetic determinants of the timing of
sexual maturation in the human.

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Insights Garnered from Kiss1 −/− and Kiss1r −/− Mice

In general, Kiss1 −/− and Kiss1r −/− mice are phenocopies of humans bearing KISS1R
mutations. Both Kiss1 −/− and Kiss1r −/− mice have small gonads, low gonadotropins,
and abnormal gametogenesis, and infertility [ 4 , 9 , 58 , 59 ]. GnRH neuronal migra-
tion into the hypothalamus is normal in Kiss1 −/− animals, along with appropriate
axonal connections to the median eminence and total GnRH content [ 58 ].
Despite their infertility, Kiss1 −/− female mice can develop follicles, up to the pre-
ovulatory level, although no spontaneous ovulations are observed [ 8 ]. Both Kiss1 −/−
and Kiss1r −/− females alternate between periods of prolonged diestrus and prolonged
estrus. These transitions increase in frequency with increasing age and are not asso-
ciated with changes in hypothalamic Gnrh1 mRNA expression. Administration of
the competitive GnRH antagonist acyline disrupts the estrus exhibited by Kiss1 −/−