Mutation analysis of the LH Receptor Gene in Leydig Cell Adenoma and Hyperplasia and Functional and Biochemical Studies of Activating Mutations of the LH Receptor Gene
| Autor: | Axel P. N. Themmen, Annette Richter-Unruh, Stenvert L. S. Drop, Ada Funaro, Serge Lumbroso, Miriam Verhoef-Post, Auke Beishuizen, Leendert H. J. Looijenga, André van Marle, Annemieke M. Boot |
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| Přispěvatelé: | Developmental Biology, Internal Medicine, Pathology, Pediatrics |
| Rok vydání: | 2011 |
| Předmět: |
Male
Endocrinology Diabetes and Metabolism Clinical Biochemistry Mutant DNA Mutational Analysis Medizin Puberty Precocious LH receptor Leydig cell adenoma signal transduction mutation analysis medicine.disease_cause Biochemistry LUTEINIZING-HORMONE RECEPTOR INDEPENDENT SEXUAL PRECOCITY Endocrinology Child Mutation JCEM Online: Advances in Genetics luteinizing hormone/choriogonadotropin receptor Leydig Cells Hyperplasia Receptors LH CANCER TUMORS Child Preschool Signal transduction Adenoma endocrine system medicine.medical_specialty SOMATIC MUTATION PATHOPHYSIOLOGY LUTROPIN-RECEPTOR Biology CAVEOLAE Germline mutation Testicular Neoplasms Internal medicine medicine Humans LUTROPIN/CHORIOGONADOTROPIN RECEPTOR Biochemistry (medical) medicine.disease PUBERTY Mutation testing |
| Zdroj: | Journal of Clinical Endocrinology and Metabolism, 96(7), E1197-E1205. ENDOCRINE SOC Journal of Clinical Endocrinology and Metabolism, 96(7), E1197-E1205. Endocrine Society |
| ISSN: | 1945-7197 0021-972X |
| Popis: | Context: Germline and somatic activating mutations in the LH receptor (LHR) gene have been reported.Objective: Our objective was to perform mutation analysis of the LHR gene of patients with Leydig cell adenoma or hyperplasia. Functional studies were conducted to compare the D578H-LHR mutant with the wild-type (WT)-LHR and the D578G-LHR mutant, a classic cause of testotoxicosis. The three main signal transduction pathways in which LHR is involved were studied.Patients: We describe eight male patients with gonadotropin-independent precocious puberty due to Leydig cell adenoma or hyperplasia.Results: The D578H-LHR mutation was found in the adenoma or nodule with hyperplasia in all but two patients. D578H-LHR displayed a constitutively increased but noninducible production of cAMP, led to a very high production of inositol phosphates, and induced a slight phosphorylation of p44/42 MAPK in the absence of human chorionic gonadotropin. The D578G-LHR showed a response intermediate between WT-LHR and the D578H-LHR. Subcellular localization studies showed that the WT-LHR was almost exclusively located at the cell membrane, whereas the D578H-LHR showed signs of internalization. D578H-LHR was the only receptor to colocalize with early endosomes in the absence of human chorionic gonadotropin.Conclusions: Although several LHR mutations have been reported in testotoxicosis, the D578H-LHR mutation, which has been found only as a somatic mutation, appears up until now to be specifically responsible for Leydig cell adenomas. This is reflected by the different activation of the signal transduction pathways, when compared with the WT-LHR or D578G-LHR, which may explain the tumorigenesis in the D578H mutant. (J Clin Endocrinol Metab 96: E1197-E1205, 2011) |
| Databáze: | OpenAIRE |
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