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males exhibiting a fi vefold higher incidence compared to females [
2
,
61
,
62
].
Approximately 60% of affected patients have associated anosmia—decreased or
absent sense of smell [
63
]. The underlying cause of the IHH in these patients is
defective developmental migration of GnRH neurons from the nasal placode to their
fi nal destination in the pre-optic area of the hypothalamus during embryonic devel-
opment [
64
]. Mutations identifi ed in patients with IHH associated with anosmia
have been traced to genes encoding proteins that regulate GnRH and olfactory neu-
ronal migration during development [
65
]. In contrast to anosmic patients, the major-
ity of mutations identifi ed in the remaining 40% of patients with a normal sense of
smell (nIHH) encode proteins that regulate GnRH secretion or action, such as the
KISS1R [
66
].
The analysis of pedigrees in families with a history of nIHH often indicates an
autosomal recessive
inheritance pattern (Table
7.1
). This pattern has been confi rmed
in families carrying inactivating mutations in KISS1R [
8
,
9
,
11
,
12
]. Affected mem-
bers of these families carry the associated loss-of-function mutation in the
homozy-
gous
(or compound heterozygous) state, whereas
heterozygous
parents and siblings
have no apparent reproductive phenotype. This suggests that one wild type allele is
suffi cient for the effect of KISS1R on GnRH secretion in heterozygous patients. On
the other hand, heterozygous mutations in
KISS1R
may contribute to milder pheno-
types [
16
,
67
].
All inactivating mutations in
KISS1R
identifi ed to date have been shown or pre-
dicted to impair G protein signaling by the receptor [
8
,
9
,
11
,
12
,
14
], indicating a
vital role of G protein signaling for GnRH secretion. Since affected patients have
normal sense of smell, inactivating mutations in this receptor do not appear to affect
GnRH neuronal migration during development. Please refer to Table
7.1
for the list
of inactivating mutations discussed below.
The Leu148Ser-KISS1R Mutation
A point mutation in the coding sequence of the
KISS1R
gene was identifi ed in the
homozygous state in all affected members of a consanguineous Saudi-Arabian fam-
ily with history of nIHH. This highly consanguineous family includes 3 marriages
of fi rst-degree cousins, who gave birth to a total of 16 children, 6 of them presenting
with symptoms compatible with complete IHH [
9
].
This point mutation resulted in the replacement of a leucine residue at position
148 of the KISS1R with a serine (Leu148Ser-KISS1R). This leucine is located
within the second intracellular loop of the receptor (Fig.
7.1
) and is highly con-
served among the members of class A GPCRs, strongly suggestive that this leucine
is essential for receptor function [
68
]. Nonetheless, heterozygous parents and sib-
lings of affected patients in this family have no apparent phenotype [
9
], in agree-
ment with the predicted autosomal recessive mode of inheritance (Table
7.1
).
Functional assays showed that the Leu148Ser-KISS1R mutant has impaired G
protein signaling, as indicated by the absence of increased inositol phosphate
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