Molecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations - Kisspeptin Signaling in Reproductive Biology - page 142

a robust LH and FSH response in this patient. Despite the positive response and the
signs of sexual maturation, this patient was able to achieve fertility only after a year
and a half of GnRH therapy [ 12 ].
Another pair of compound heterozygous mutations was identifi ed in a boy with
hypogonadism [ 13 ]. One allele had leucine replacing the normal arginine at position
297 (Arg297Leu) whereas the other allele had arginine replacing the normal cyste-
ine at position 223 of the KISS1R (Cys223Arg) (Fig. 7.1 ). The affected boy was
born with microphallus and cryptorchidism, and had undetectable serum gonadotro-
pins at 2 months of age [ 13 ]. Evaluation at age 10 years showed poor gonadotropin
and testosterone response to GnRH or hCG stimulation. The boy's mother and a
younger brother, both heterozygous for the Arg297Leu mutation, had no signs of
hypogonadism [ 13 ].
Calcium release by the Cys223Arg-KISS1R mutant was shown to be impaired.
The mutant receptor required 40 times more kisspeptin to reach the response level
of the wild-type KISS1R (i.e., EC 50 was 40-fold lower for the Cys223Arg KISS1R
mutant) [ 13 ]. Although the mutation in the second allele—Arg297Leu—only
slightly impaired KISS1R signaling, the combination with the Cys223Arg KISS1R
was associated with hypogonadism (Table 7.1 ).
Loss-of-Function due to Frame-Shift in the KISS1R Gene
The deletion or insertion of nucleotides within the coding region of the KISS1R has
also been associated with the nIHH phenotype in patients due to loss-of-function of
the receptor protein [ 8 , 10 ]. The fi rst description of a deletion in the coding sequence
of the KISS1R gene was published in 2003 [ 8 ]. The deletion was identifi ed in the
homozygous state in all fi ve affected children of a consanguineous family of eight
children.
The four affected males of this family had a phenotype compatible with com-
plete IHH with a normal sense of smell as well as a blunted response to GnRH
stimulation [ 8 ]. Despite the manifestations of hypogonadism, the only affected
female showed signs of partial sexual maturation, such as an episode of uterine
bleeding and partial breast development [ 8 ]. Her serum estradiol was above prepu-
bertal levels and her LH response to an intravenous injection of GnRH was unusu-
ally robust [ 8 , 67 ]. Interestingly, the heterozygous mother of these children had
delayed puberty (menarche at 16 years of age), whereas the heterozygous father
reported normal pubertal development [ 8 ].
The KISS1R deletion in this family eliminated 155 nucleotides of the KISS1R
gene, starting within intron 4 and including the splice acceptor site between intron
4 and exon 5, as well as part of the coding sequence of exon 5 (Table 7.1 ) [ 8 ].
Although functional assays have not been performed for this mutant, the deletion of
the splice acceptor site between intron 4 and exon 5 would be expected to eliminate
all amino acids encoded by exon 5 from the protein. If expressed, this mutant may
be truncated at the end of the fourth exon, which corresponds to the glutamic acid at