GNRH1 mutations in patients with idiopathic hypogonadotropic hypogonadism.
Idiopathic hypogonadotropic hypogonadism (IHH) is a condition characterized by failure to undergo puberty in the setting of low sex steroids and low gonadotropins. IHH is due to abnormal secretion or action of the master reproductive hormone gonadotropin-releasing hormone (GnRH). Several genes have been found to be mutated in patients with IHH, yet to date no mutations have been identified in the most obvious candidate gene, GNRH1 itself, which encodes the preprohormone that is ultimately processed to produce GnRH. We screened DNA from 310 patients with normosmic IHH (nIHH) and 192 healthy control subjects for sequence changes in GNRH1. In 1 patient with severe congenital nIHH (with micropenis, bilateral cryptorchidism, and absent puberty), a homozygous frameshift mutation that is predicted to disrupt the 3 C-terminal amino acids of the GnRH decapeptide and to produce a premature stop codon was identified. Heterozygous variants not seen in controls were identified in 4 patients with nIHH: 1 nonsynonymous missense mutation in the eighth amino acid of the GnRH decapeptide, 1 nonsense mutation that causes premature termination within the GnRH-associated peptide (GAP), which lies C-terminal to the GnRH decapeptide within the GnRH precursor, and 2 sequence variants that cause nonsynonymous amino-acid substitutions in the signal peptide and in GnRH-associated peptide. Our results establish mutations in GNRH1 as a genetic cause of nIHH.
Chan
Yee-Ming
YM
Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
de Guillebon
Adelaide
A
Lang-Muritano
Mariarosaria
M
Plummer
Lacey
L
Cerrato
Felecia
F
Tsiaras
Sarah
S
Gaspert
Ariana
A
Lavoie
Hélène B
HB
Wu
Ching-Hui
CH
Crowley
William F
WF
Amory
John K
JK
Pitteloud
Nelly
N
Seminara
Stephanie B
SB
D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D012739:Gonadal Steroid Hormones / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics*; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D011498:Protein Precursors / Q000235:genetics*; D012903:Smell / Q000235:genetics
D017931:DNA Primers; D012739:Gonadal Steroid Hormones; D011498:Protein Precursors; C050866:progonadoliberin I; D007987:Gonadotropin-Releasing Hormone