Molecular Biology of the Kisspeptin Receptor: Signaling, Function, and Mutations - Kisspeptin Signaling in Reproductive Biology - page 143

position 246 of the KISS1R (Fig. 7.1 ). Such a truncated receptor would be missing
half of the third intracellular loop, the sixth and seventh transmembrane domains
and the carboxyl terminal tail of the KISS1R, which would likely result in receptor
misfolding and degradation, or impaired activity.
A homozygous insertion of a cytosine after nucleotide 1001 (1001_1002insC)
was identifi ed in the KISS1R gene of a patient born to a family with no history of
IHH (Table 7.1 ) [ 10 ]. However, the parents of this patient were second-degree cous-
ins, which suggests that they may be asymptomatic heterozygous carriers of the
mutation. If expressed, this mutant would result in a frame-shift that could poten-
tially increase the size of the KISS1R protein from 398 to 441 amino acids [ 10 ]. The
affected patient presented with congenital hypogonadotropic hypogonadism as
indicated by the undescended testes and mild hypospadias, with subsequent delayed
puberty as well as impaired fertility. Semen analysis revealed oligoasthenozoosper-
mia (low concentration and reduced motility of spermatozoids) [ 10 ]. The patient's
phenotype indicates that the nucleotide insertion results in profound impairment of
KISS1R function when present in the homozygous state, despite the absence of
hypogonadism in the presumably heterozygous parents. Nonetheless, this patient
was able to father a child by in vitro fertilization after 2 years of pulsatile GnRH
therapy [ 10 ].
An insertion/deletion within the splice acceptor site of the 3

-end of intron 2 of
KISS1R was identifi ed in two brothers presenting with absent sexual maturation as
well as prepubertal serum testosterone levels and low gonadotropins at ages 14 and
20 years [ 15 ]. In this family, the nucleotides at position −2 to −4 (GCA) within the
3'-splice acceptor site of intron 2 were missing. In their place was the insertion of a
5-nucleotide sequence (ACCGGT) (Table 7.1 ). This mutation is predicted to disrupt
normal splicing, resulting in the use of alternative acceptor sites and the generation
of aberrant KISS1R proteins. The mother was heterozygous for the same deletion/
insertion but reported normal sexual maturation [ 15 ].

′

Mutations in KISS1R not Associated with Altered Function

Some KISS1R mutations identifi ed in IHH patients have not yet been associated
with altered receptor function, such as Glu252Gln KISS1R. This mutation was
identifi ed in the heterozygous state in a patient with sporadic IHH [ 15 ]. However,
functional assays performed for this mutant did not detect any changes in activity.
Furthermore, the presence of the mutation in the heterozygous state, with the other
allele being normal, is in disagreement with the predicted autosomal recessive
inheritance mode. This suggests that this patient may carry additional yet-to-be-
identifi ed mutation(s) or polymorphism(s) associated with the IHH phenotype.
Other amino acid substitutions identifi ed in patients with reproductive disorders
have also been found in control populations and thus are considered to be normal
variants, such as the His364Leu KISS1R variant [ 13 , 15 ].