TY - JOUR
T1 - Genotype and phenotype of patients with gonadotropin-releasing hormone receptor mutations
AU - Kim, Hyung Goo
AU - Pedersen-White, Jennifer
AU - Bhagavath, Balasubramanian
AU - Layman, Lawrence C.
PY - 2010/4/8
Y1 - 2010/4/8
N2 - Human mutations in the gonadotropin-releasing hormone receptor (GNRHR) gene cause autosomal recessive, normosmic idiopathic hypogonadotropic hypogonadism (IHH). At least 19 different mutations have been identified in this G-protein-coupled receptor, which consist mostly of missense mutations. The Gln106Arg and Arg262Gln mutations comprise nearly half of the identified alleles. Most mutations impair ligand binding and all compromise cell signaling events. Some of the mutations also adversely affect activation of gonadotropin subunit or Gnrhr gene promoters. Interestingly, a number of the mutant GnRHRs can be rescued in vitro from misfolding and degradation within the cell by the addition of a GnRHR antagonist IN3. Most affected patients have compound heterozygous GNRHR mutations that may cause either complete IHH (no evidence of puberty) or incomplete IHH (partial evidence of puberty), although some genotypes are associated with mild disease in some families and severe disease in others. GNRHR mutations also appear to cause constitutional delay of puberty, and one genotype (homozygosity for Gln106Arg) may be reversible in patients with IHH. Mutations in the human GNRHR gene have contributed greatly to the understanding of normosmic IHH, as well as the structure and function of the GnRHR.
AB - Human mutations in the gonadotropin-releasing hormone receptor (GNRHR) gene cause autosomal recessive, normosmic idiopathic hypogonadotropic hypogonadism (IHH). At least 19 different mutations have been identified in this G-protein-coupled receptor, which consist mostly of missense mutations. The Gln106Arg and Arg262Gln mutations comprise nearly half of the identified alleles. Most mutations impair ligand binding and all compromise cell signaling events. Some of the mutations also adversely affect activation of gonadotropin subunit or Gnrhr gene promoters. Interestingly, a number of the mutant GnRHRs can be rescued in vitro from misfolding and degradation within the cell by the addition of a GnRHR antagonist IN3. Most affected patients have compound heterozygous GNRHR mutations that may cause either complete IHH (no evidence of puberty) or incomplete IHH (partial evidence of puberty), although some genotypes are associated with mild disease in some families and severe disease in others. GNRHR mutations also appear to cause constitutional delay of puberty, and one genotype (homozygosity for Gln106Arg) may be reversible in patients with IHH. Mutations in the human GNRHR gene have contributed greatly to the understanding of normosmic IHH, as well as the structure and function of the GnRHR.
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U2 - 10.1159/000312696
DO - 10.1159/000312696
M3 - Article
C2 - 20389088
AN - SCOPUS:84925955981
SN - 0301-3073
VL - 39
SP - 94
EP - 110
JO - Frontiers of Hormone Research
JF - Frontiers of Hormone Research
ER -