Novel homozygous splice acceptor site GnRH receptor (GnRHR) mutation: Human GnRHR knockout

Mutations in the GnRH receptor (GnRHR) have been shown to be responsible for a significant number of autosomic recessive and, less commonly, sporadic cases of idiopathic hypogonadotropic hypogonadism. We describe a woman with complete GnRH resistance secondary to a novel homozygous GnRHR gene mutati...

Full description

Saved in:
Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 2002-06, Vol.87 (6), p.2973-2977
Main Authors: SILVEIRA, L. F. G, STEWART, P. M, THOMAS, M, CLARK, D. A, BOULOUX, P. M. G, MACCOLL, G. S
Format: Article
Language:English
Subjects:
Adolescent
Amenorrhea - genetics
Base Sequence - genetics
Biological and medical sciences
DNA - genetics
Female
Gene Expression
Genes, Recessive
Gonadotropins - secretion
Gynecology. Andrology. Obstetrics
Homozygote
Humans
Hypogonadism - genetics
Male and female genital diseases. Gonadal dysgenesis. Hermaphroditism. Sex hormones resistance
Medical sciences
Mutation
Pedigree
Receptors, LHRH - genetics
RNA Splice Sites
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Mutations in the GnRH receptor (GnRHR) have been shown to be responsible for a significant number of autosomic recessive and, less commonly, sporadic cases of idiopathic hypogonadotropic hypogonadism. We describe a woman with complete GnRH resistance secondary to a novel homozygous GnRHR gene mutation, transmitted as an autosomal recessive trait. The propositus presented with primary amenorrhea and absent thelarche and pubarche. Dynamic tests demonstrated absent spontaneous gonadotropin pulsatility, and no response to either exogenous pulsatile (10 microg/pulse at 90-min intervals over 6 h) or acute (100 microg) GnRH administration. However, she responded to exogenous gonadotropin administration, with a resulting normal pregnancy. Genomic DNA extracted from peripheral blood was PCR amplified using amplimers spanning intron-exon boundaries for the three exons of GnRHR and revealed a homozygous splice junction mutation (G to A transversion) at the intron 1-exon 2 boundary. Her unaffected sister, with a totally normal phenotype, was heterozygous for this mutation. After lymphocyte Epstein-Barr virus transformation, RNA was extracted and subjected to RT-PCR, using primers located in the first and third exons. Results showed a transcript lacking all of exon 2 (exon 2 skipping), with splicing of exon 1 to exon 3. This created a frame shift, generating a coding sequence for three new amino acids, followed by a stop codon. Although it is not clear whether the mutant receptor is actually expressed, the resultant mRNA sequence was presumed to produce a truncated receptor with no binding or signaling capacity.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.87.6.2973