Two families with normosmic congenital hypogonadotropic hypogonadism and biallelic mutations in KISS1R (KISS1 receptor): clinical evaluation and molecular characterization of a novel mutation.
BACKGROUND
KISS1R mutations have been reported in few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110).


OBJECTIVE
To describe in detail nCHH patients with biallelic KISS1R mutations belonging to 2 unrelated families, and to functionally characterize a novel KISS1R mutation.


RESULTS
An original mutant, p.Tyr313His, was found in the homozygous state in 3 affected kindred (2 females and 1 male) from a consanguineous Portuguese family. This mutation, located in the seventh transmembrane domain, affects a highly conserved amino acid, perturbs the conformation of the transmembrane segment, and impairs MAP kinase signaling and intracellular calcium release. In the second family, a French Caucasian male patient with nCHH was found to carry two recurrent mutations in the compound heterozygous state (p.Leu102Pro/Stop399Arg). In this man, pulsatile GnRH (Gonadotropin Releasing Hormone) administration restored pulsatile LH (Luteinizing Hormone) secretion and testicular hormone secretion. Later, long-term combined gonadotropin therapy induced spermatogenesis, enabling 3 successive pregnancies that resulted in 2 miscarriages and the birth of a healthy boy.


CONCLUSIONS
We show that a novel loss-of-function mutation (p.Tyr313His) in the KISS1R gene can cause familial nCHH, revealing the crucial role of this amino acid in KISS1R function. The observed restoration of gonadotropin secretion by exogenous GnRH administration further supports, in humans, the hypothalamic origin of the gonadotropin deficiency in this genetic form of nCHH.
Paris-Sud UMR-S693, Univ Paris-Sud, Le Kremlin Bicêtre, France.
Frédéric
F
Brioude
Jérôme
J
Bouligand
Bruno
B
Francou
Jérôme
J
Fagart
Ronan
R
Roussel
Say
S
Viengchareun
Laurent
L
Combettes
Sylvie
S
Brailly-Tabard
Marc
M
Lombès
Jacques
J
Young
Anne
A
Guiochon-Mantel
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007006:Hypogonadism / Q000151:congenital / Q000235:genetics*; D059648:Kisspeptins / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics*; D000074502:Receptors, Kisspeptin-1; D017386:Sequence Homology, Amino Acid
C106628:KISS1 protein, human; C118688:KISS1R protein, human; D059648:Kisspeptins; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium