Molecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations - Kisspeptin Signaling in Reproductive Biology - page 141

A male patient born to an unrelated consanguineous family and also carrying the
Leu102Pro mutation in the homozygous state presented with congenital hypogo-
nadism, as indicated by micropenis and bilateral cryptorchidism at birth [ 14 ].
Testosterone treatment did not produce signifi cant changes in testicular volume or
facial hair growth in this patient, despite improving his pubic hair growth. He had
two sisters with primary amenorrhea, one with incomplete pubertal development
and the other with a history of infertility for 5 years [ 14 ]. All affected siblings car-
ried the Leu102Pro KISS1R mutation in the homozygous state. Interestingly, the
females in this family appear to have a milder phenotype when compared to their
brother.
The Phe272Ser-KISS1R Mutation
A recent study identifi ed a novel loss-of-function single amino acid substitution in
KISS1R in six patients from two related and highly consanguineous families
(Table 7.1 ) [ 11 ]. All fi ve affected males and the one affected female were shown to
carry the Phe272Ser KISS1R mutation in the homozygous state, whereas heterozy-
gous parents and siblings had no apparent reproductive phenotype [ 11 ]. The replace-
ment of phenylalanine at position 272 of KISS1R with serine (Fig. 7.1 ) resulted in
cryptorchidism, short penis, azoospermia, gonadotropin defi ciency, and no sponta-
neous pubertal development in all affected males, whereas the affected female
exhibited primary amenorrhea with low basal LH and undetectable estradiol at age
18 [ 11 ]. Functional assays showed impaired G q signaling by the Phe272Ser-KISS1R
mutant, which also lacked membrane localization as indicated by immunofl uores-
cence imaging [ 11 ]. Despite the severity of the phenotype in homozygous carriers,
pubertal development of a heterozygous male sibling was not affected, again con-
fi rming the predicted autosomal recessive inheritance mode.
Compound Heterozygous KISS1R Mutations and IHH
The combination of two distinct mutations carried by separate alleles may also
result in loss-of-function. Called compound heterozygous , such mutations have
been identifi ed in KISS1R in association with the IHH phenotype. An example is the
insertion of a stop codon in exchange for the normal arginine at position 331 of the
KISS1R on one allele (Arg331X) (Fig. 7.1 ), whereas the other allele had the normal
stop codon replaced with an arginine (X399Arg) in a patient with IHH (Table 7.1 )
[ 9 ]. The introduction of the stop codon at position 331 generates a truncated recep-
tor, whereas the replacement of the normal stop codon could result in receptor mis-
folding, as functional assays revealed impaired signaling by both mutants [ 9 ]. The
affected male patient presented with azoospermia with germinal hypoplasia and had
no LH pulses [ 12 ]. Nonetheless, a single intravenous injection of GnRH resulted in