LH Receptor Defects

Themmen, Axel P. N.; Verhoef-Post, Miriam

doi:10.1055/s-2002-35384

Cited by 51 publications

(15 citation statements)

References 26 publications

(35 reference statements)

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“…In most cases the gain of function is related to conversion of the wild-type receptor that is dependent on agonist stimulation to a constitutively active receptor that is not dependent on activating ligand. Gain-of-function disorders include constitutively active rhodopsin, which can cause night blindness, 123 constitutively active parathyroid hormone-related receptor, which causes Jansen-type metaphyseal chondrodysphsin, 124 constitutively active thyroid-stimulating hormone and follicle-stimulating hormone receptors, causing congenital hyperthyroidism 125 and familial male precocious puberty, 126 and mutations in the calcium sensing GPCR that cause hypocalciuric hypercalcemia and neonatal hyperparathyroidism. 127 For these diseases, development of inverse agonists could be useful as therapeutics since they would be predicted to selectively block the actions of the constitutively active receptor.…”

Section: Gpcr Mutations Disease and Novel Drug Discoverymentioning

confidence: 99%

Emerging Concepts of Guanine Nucleotide-Binding Protein-Coupled Receptor (GPCR) Function and Implications for High Throughput Screening

Eglen

Bossé

Reisine³

2007

ASSAY and Drug Development Technologies

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Guanine nucleotide binding protein (G protein) coupled receptors (GPCRs) comprise one of the largest families of proteins in the human genome and are a target for 40% of all approved drugs. GPCRs have unique structural motifs that allow them to interact with a wide and diverse series of extracellular ligands, as well as intracellular proteins, G proteins, receptor activity-modifying proteins, arrestins, and indeed other receptors. This distinctive structure has led to numerous efforts to discover drugs against GPCRs with targeted therapeutic uses. Such "designer" drugs currently include allosteric regulators, inverse agonists, and drugs targeting hetero-oligomeric complexes. Moreover, the large family of orphan GPCRs provides a rich and novel field of targets to discover drugs with unique therapeutic properties. The numerous technologies to discover GPCR drugs have also greatly advanced over the years, facilitating compound screening against known and orphan GPCRs, as well as in the identification of unique designer GPCR drugs. Indeed, high throughput screening (HTS) technologies employing functional cell-based approaches are now widely used. These include measurement of second messenger accumulation such as cyclic AMP, calcium ions, and inositol phosphates, as well as mitogen-activated protein kinase activation, protein-protein interactions, and GPCR oligomerization. This review focuses on how the improved understanding of the molecular pharmacology of GPCRs, coupled with a plethora of novel HTS technologies, is leading to the discovery and development of an entirely new generation of GPCR-based therapeutics.

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Section: Gpcr Mutations Disease and Novel Drug Discoverymentioning

confidence: 99%

Emerging Concepts of Guanine Nucleotide-Binding Protein-Coupled Receptor (GPCR) Function and Implications for High Throughput Screening

Eglen

Bossé

Reisine³

2007

ASSAY and Drug Development Technologies

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“…Previously, we and others have used genetic models, including FSH␤, FSH-receptor, and LHreceptor knockout mice, to study the physiological roles of gonadotropins in gonad development and function (11)(12)(13)(14)(15). Whereas FSH␤ and FSH-receptor knockout mice mostly phenocopy human ovarian dysgenesis disease (16,17), LH-receptor mutant mice demonstrate most of the phenotypes associated with inactivating LH-receptor mutations in human males, including Leydig cell hypoplasia (18,19). Only a single male patient with an inactivating mutation in the LH␤ gene has been described (20).…”

mentioning

confidence: 99%

Targeted disruption of luteinizing hormone β-subunit leads to hypogonadism, defects in gonadal steroidogenesis, and infertility

Dong

Matzuk

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

300

209

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Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) act on gonadal cells to promote steroidogenesis and gametogenesis. Clarifying the in vivo roles of LH and FSH permits a feasible approach to contraception involving selective blockade of gonadotropin action. One way to address these physiologically important problems is to generate mice with an isolated LH deficiency and compare them with existing FSH loss-of-function mice. To model human reproductive disorders involving loss of LH function and to define LH-responsive genes, we produced knockout mice lacking the hormone-specific LH␤-subunit. LH␤-null mice are viable but demonstrate postnatal defects in gonadal growth and function resulting in infertility. Mutant males have decreased testes size, prominent Leydig cell hypoplasia, defects in expression of genes encoding steroid biosynthesis pathway enzymes, and reduced testosterone levels. Furthermore, spermatogenesis is blocked at the round spermatid stage, causing a total absence of the elongated spermatids. Mutant female mice are hypogonadal and demonstrate decreased levels of serum estradiol and progesterone. Ovarian histology demonstrates normal thecal layer, defects in folliculogenesis including many degenerating antral follicles, and absence of corpora lutea. The defects in both sexes are not secondary to aberrant FSH regulation, because FSH levels were unaffected in null mice. Finally, both male and female null mice can be pharmacologically rescued by exogenous human chorionic gonadotropin, indicating that LH-responsiveness of the target cells is not irreversibly lost. Thus, LH␤ null mice represent a model to study the consequences of an isolated deficiency of LH ligand in reproduction, while retaining normal LH-responsiveness in target cells.is a member of the glycoprotein hormone family that includes follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (1, 2). These hormones are heterodimers consisting of a common ␣-subunit noncovalently linked to a hormone-specific ␤-subunit. LH binds to G-protein coupled receptors on Leydig cells in the testis and granulosa and theca cells in the ovary (1, 2). During pubertal and postpubertal gonad development, LH promotes steroidogenesis required for normal reproductive function (1, 2). Less clear are its functions during embryonic gonad development, although evidence suggests that early gonad development is independent of gonadotropin stimulation (3, 4).Intercellular communication within the testis is essential for normal spermatogenesis (5, 6). In response to FSH, the Sertoli cells secrete various factors that affect Leydig cell function (7,8). Similarly, testosterone produced from Leydig cells is required for spermatogenesis (7,8). In females, ovarian folliculogenesis and ovulation are critically dependent on synchronized activities of both FSH and LH (9, 10). Previously, we and others have used genetic models, including FSH␤, FSH-receptor, and LHreceptor knockout mice, to study the physiological roles of gonadotropins in gonad developmen...

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“…Les derives Mulleriens sont absents. Des derives wolffiens rudimentaires ont ete observes chez certains patients en depit de I'existence d'organes genitaux externes feminins [2].…”

Section: Observationunclassified