Novel homozygous splice acceptor site GnRH receptor (GnRHR) mutation: human GnRHR 'knockout'
| Autor: | P.-M. G. Bouloux, Leticia Ferreira Gontijo Silveira, Paul M. Stewart, M. Thomas, G. S. MacColl, Duncan A. Clark |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
medicine.medical_specialty
Adolescent Endocrinology Diabetes and Metabolism Clinical Biochemistry Gene Expression Genes Recessive Biology medicine.disease_cause Biochemistry Frameshift mutation Exon Autosomal recessive trait Endocrinology Hypogonadotropic hypogonadism Internal medicine medicine Humans Amenorrhea Genetics Mutation Base Sequence Hypogonadism Biochemistry (medical) GNRHR Homozygote Intron DNA medicine.disease Stop codon Pedigree Female RNA Splice Sites Gonadotropins Receptors LHRH |
| Zdroj: | The Journal of clinical endocrinology and metabolism. 87(6) |
| ISSN: | 0021-972X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|