Isolated familial hypogonadotropic hypogonadism and a GNRH1 mutation.
We investigated whether mutations in the gene encoding gonadotropin-releasing hormone 1 (GNRH1) might be responsible for idiopathic hypogonadotropic hypogonadism (IHH) in humans. We identified a homozygous GNRH1 frameshift mutation, an insertion of an adenine at nucleotide position 18 (c.18-19insA), in the sequence encoding the N-terminal region of the signal peptide-containing protein precursor of gonadotropin-releasing hormone (prepro-GnRH) in a teenage brother and sister, who had normosmic IHH. Their unaffected parents and a sibling who was tested were heterozygous. This mutation results in an aberrant peptide lacking the conserved GnRH decapeptide sequence, as shown by the absence of immunoreactive GnRH when expressed in vitro. This isolated autosomal recessive GnRH deficiency, reversed by pulsatile GnRH administration, shows the pivotal role of GnRH in human reproduction.
Bouligand
Jérôme
J
Université Paris-Sud, Faculté de Médecine Paris-Sud and Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, INSERM UMR-S693, Paris, France.
Ghervan
Cristina
C
Tello
Javier A
JA
Brailly-Tabard
Sylvie
S
Salenave
Sylvie
S
Chanson
Philippe
P
Lombès
Marc
M
Millar
Robert P
RP
Guiochon-Mantel
Anne
A
Young
Jacques
J
D000293:Adolescent; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D016368:Frameshift Mutation; D005808:Genes, Recessive; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000172:deficiency / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism; D008297:Male; D010375:Pedigree; D011498:Protein Precursors / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013739:Testosterone / Q000097:blood
D011498:Protein Precursors; C050866:progonadoliberin I; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone