Linked Life Data

15240592

Source:http://linkedlifedata.com/resource/pubmed/id/15240592

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2004-7-8
pubmed:abstractText
Mutations in the GnRH receptor gene (GNRHR) are a cause of idiopathic hypogonadotropic hypogonadism. We describe a normosmic female subject with congenital idiopathic hypogonadotropic hypogonadism in whom treatment with pulsatile GnRH resulted in an unusual response. The subject not only required an increased dose of pulsatile GnRH for ovarian follicular development, but LH secretion did not increase appropriately, estradiol levels remained low, and she did not ovulate spontaneously. Sequencing of the GNRHR coding sequence revealed compound heterozygous mutations leading to amino acid substitutions [N10K+Q11K] and P320L. The introduction of the P320L mutation into the GnRH receptor led to failure of detectable ligand binding and failure of stimulation of inositol phosphate production and gonadotropin subunit gene promoter activity in response to GnRH in transiently transfected cells. The [N10K+Q11K] mutation resulted in reduced binding of a GnRH agonist to 25% of the wild-type receptor. In addition, the EC(50) value for GnRH stimulation of inositol phosphate production was significantly increased, and the dose-response curves for stimulation of alpha gonadotropin subunit, LHbeta, and FSHbeta gene transcription by GnRH were similarly shifted to the right. Stimulation of FSHbeta gene transcription was more sensitive to GnRH than LHbeta for both wild-type and [N10K+Q11K] GnRH receptors, resulting in a greater loss of LHbeta stimulation than FSHbeta by the [N10K+Q11K] mutant at any given submaximal GnRH concentration. We propose that the mutations in the GnRH receptor result in a rightward shift of the dose-response curves of gonadotropin responses to pulsatile GnRH in the subject and unmask the differential sensitivities of LH and FSH to GnRH, resulting in low LH and estradiol levels despite appropriate FSH secretion and follicular growth.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0021-972X
pubmed:author
pubmed:issnType
Print
pubmed:volume
89
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3189-98
pubmed:dateRevised
2009-11-3
pubmed:meshHeading
pubmed-meshheading:15240592-Adult, pubmed-meshheading:15240592-Amino Acid Sequence, pubmed-meshheading:15240592-Amino Acid Substitution, pubmed-meshheading:15240592-Base Sequence, pubmed-meshheading:15240592-Case-Control Studies, pubmed-meshheading:15240592-Cell Membrane, pubmed-meshheading:15240592-Cells, Cultured, pubmed-meshheading:15240592-DNA, pubmed-meshheading:15240592-Dose-Response Relationship, Drug, pubmed-meshheading:15240592-Estradiol, pubmed-meshheading:15240592-Female, pubmed-meshheading:15240592-Follicle Stimulating Hormone, pubmed-meshheading:15240592-Follicle Stimulating Hormone, beta Subunit, pubmed-meshheading:15240592-Gonadotropin-Releasing Hormone, pubmed-meshheading:15240592-Heterozygote, pubmed-meshheading:15240592-Humans, pubmed-meshheading:15240592-Hypogonadism, pubmed-meshheading:15240592-Inositol Phosphates, pubmed-meshheading:15240592-Luteinizing Hormone, pubmed-meshheading:15240592-Luteinizing Hormone, beta Subunit, pubmed-meshheading:15240592-Mutation, pubmed-meshheading:15240592-Receptors, LHRH
pubmed:year
2004
pubmed:articleTitle
GNRHR mutations in a woman with idiopathic hypogonadotropic hypogonadism highlight the differential sensitivity of luteinizing hormone and follicle-stimulating hormone to gonadotropin-releasing hormone.
pubmed:affiliation
Reproductive Endocrine Unit, Bartlett Hall Extension 5, Massachusetts General Hospital, Boston, MA 02114, USA. ameysing@partners.org
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Case Reports, Research Support, Non-U.S. Gov't