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production in response to kisspeptin stimulation in cells transfected with this mutant
receptor [
9
]. On the other hand, biochemical and immunocytochemical assays dem-
onstrated that this mutation did not affect expression levels, ligand binding, or inter-
action of KISS1R with arrestin [
58
,
68
]. However, studies using fl uorescence
resonance energy transfer (FRET assay) indicate that this mutation prevents
kisspeptin-induced activation of G
α
q
[
68
]. Accordingly, substitution of the corre-
sponding leucine in the second intracellular loop of the
α
1A
-adrenergic receptor,
another member of the class A GPCR family, mimics the effects of the Leu148Ser
mutation on KISS1R function, suggesting that leucine in this position may belong
to a functional motif within the second intracellular loop of class A GPCRs with a
role in G protein coupling and/or activation of G protein by ligand [
68
].
The Leu148Ser-KISS1R Mutant and Fertility After Therapy
Treatment of four male members of the Saudi-Arabian family carrying the homozy-
gous Leu148Ser-KISS1R mutation with exogenous gonadotropins resulted in tes-
ticular maturation, spermatogenesis, ejaculation, and subsequent fertility [
12
].
Similarly, an affected female from this family was able to ovulate, and later become
pregnant upon pulsatile GnRH treatment followed by exogenous gonadotropin ther-
apy. She had two unsuccessful pregnancies before carrying a pregnancy to term and
delivering a healthy baby. The fi rst was an ectopic pregnancy and the second gesta-
tion was lost spontaneously at 6 months [
12
], raising the possibility that some of her
reproductive defects may not have been fully reversed by her treatments. Nonetheless,
she was able to conceive a second child years later, which was delivered by cesarean
section [
12
].
The Leu102Pro KISS1R Mutation
A single amino acid substitution in KISS1R (Leu102Pro) identifi ed in patients with
normosmic IHH and born to consanguineous marriages was also shown to result in
loss of function (Table
7.1
) [
12
,
14
]. Located on the fi rst extracellular loop of
KISS1R (Fig.
7.1
; Table
7.1
), this mutation decreases membrane expression of the
KISS1R and impairs receptor signaling [
14
]. As observed for other loss-of-function
mutations in KISS1R, heterozygous carriers of Leu102Pro KISS1R have no appar-
ent reproductive phenotype, whereas homozygous carriers present with partial or
complete gonadotropin defi ciency [
14
].
A female carrying the Leu102Pro KISS1R mutation in the homozygous state
was born to fi rst-degree cousins and presented with primary amenorrhea and incom-
plete pubertal development. After steroid supplementation for 6 months and two
cycles of GnRH stimulation, this patient was able to ovulate and become pregnant.
She was able to carry two pregnancies to term and deliver healthy babies [
14
].
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