Kisspeptin and Clinical Disorders - Kisspeptin Signaling in Reproductive Biology - page 186

genes for GnRH defi ciency; for example, KAL1 has been reported to harbor mutations
in 5-14% of GnRH-defi cient patients [ 28 - 30 ], considerably higher than the 1%
frequency of mutations in KISS1R [ 28 ]. It is unclear why the prevalence of mutations
in the kisspeptin signaling pathway is relatively low, but it is possible that kisspeptin's
role in trophoblast invasion [ 31 , 32 ] or metastasis suppression [ 33 , 34 ] creates nega-
tive selection pressure against the promulgation of mutations in families.
Reported biallelic mutations of KISS1R include a homozygous 155 base pair
deletion [ 3 ], a homozygous frameshift (c.1001_1002insC) [ 35 ], a homozygous
splice acceptor site mutation [ 36 ], homozygous p.L102P [ 37 ], p.L148S [ 4 , 38 , 39 ]
and p.F272S missense mutations [ 40 ], and the compound heterozygous mutations
p.R331X/p.X399R [ 4 , 39 ] and p.R297L/p.C223R [ 41 ]. Thus, mutations in this G
protein-coupled receptor are variable in type (large deletion, frameshift, splice site,
nonsense, nonstop, and missense) and occur throughout the receptor.
Typically, patients carrying biallelic complete loss-of-function mutations serve
as the “phenotypic bookends” of the most extreme clinical presentation that can be
associated with loss of a particular gene. In general, complete loss of kisspeptin
signaling is associated with normosmic GnRH defi ciency, but, as noted earlier, the
abnormalities in GnRH secretion may be partial. For example, an affected female
carrying a homozygous 155 base pair deletion in KISS1R (that if translated, would
lead to a truncated G protein-coupled receptor unable to stimulate the transduction
pathway) presented with some partial breast development and one episode of uter-
ine bleeding [ 3 ]. Although her sexual maturation was clearly abnormal, her breast
development and uterine bleeding suggest her endogenous estradiol levels were
above pre-pubertal values. Another female, this time carrying a homozygous L102P
mutation, demonstrated a robust LH level in response to a 100

g GnRH stimulation
test (peak approximately 32 IU/L) at initial evaluation [ 37 ]. During 6 h of frequent
blood sampling, she manifested low-amplitude LH pulses occurring approximately
once per hour. These clinical clues all suggest the presence of some degree of enfee-
bled endogenous GnRH secretion.
To date, patients with biallelic mutations in KISS1R lack the syndromic features that
can be found in anosmic forms of this disorder (Kallmann syndrome), including cleft
lip and palate, synkinesia, and renal agenesis. This is likely due to the fact that muta-
tions in the kisspeptin signaling pathway do not affect olfactory bulb development and
by extension, GnRH neuronal migration, a hypothesis supported by studies of Kiss1r − /−
mice, which have normal GnRH hypothalamic content and preserved anatomy [ 4 , 55 ,
56 ]. However, because GnRH defi ciency can be an oligogenic disease [ 28 ], it is pos-
sible that patients with Kallmann syndrome carry mutations in genes that affect not
only GnRH neuronal migration but also kisspeptin signaling [ 42 ].

μ

Discovery of Mutations in Closely Related Pathways

Kisspeptin is now appreciated to be co-expressed with other neuropeptides that are
likely to work in a cooperative fashion to regulate the hypothalamic control of repro-
duction. Kisspeptin neurons in the ARC co-express the neuropeptides neurokinin B