Association of the M1VPRKAR1AMutation with Primary Pigmented Nodular Adrenocortical Disease in Two Large Families
| Autor: | Anelia Horvath, Eirini I. Bimpaki, Alberto M. Pereira, Constantine A. Stratakis, Johannes W. A. Smit, Elizabeth Greene, Johannes A. Romijn, Maria Nesterova, Sosipatros Boikos, Anton Alatsatianos, Sanne A. Woortman, Frederik J. Hes |
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| Přispěvatelé: | Clinical sciences, General Internal Medicine |
| Rok vydání: | 2010 |
| Předmět: |
Adrenal Cortex Diseases
Adult Male medicine.medical_specialty Genetic Linkage Cyclic AMP-Dependent Protein Kinase RIalpha Subunit Endocrinology Diabetes and Metabolism Clinical Biochemistry Point Mutation/physiology Biology medicine.disease_cause Cyclic AMP-Dependent Protein Kinase RIalpha Subunit/genetics Biochemistry Adrenal Cortex Diseases/genetics Methionine/genetics Germline Young Adult Methionine Endocrinology Germline mutation subunit type 1a dependent protein-kinase carney complex regulatory subunit cushings-syndrome a pka gene endocrine tumors tissues Internal medicine medicine Humans Point Mutation Family Genetic Predisposition to Disease Amino Acid Substitution/genetics Carney complex PRKAR1A Medicine(all) Mutation Brief Report Point mutation Biochemistry (medical) Valine Valine/genetics Middle Aged medicine.disease Pedigree Amino Acid Substitution Mutation testing Female Primary pigmented nodular adrenocortical disease |
| Zdroj: | Journal of Clinical Endocrinology and Metabolism, 95(1), 338-342 Journal of clinical endocrinology and metabolism, 95(1), 338-342. The Endocrine Society |
| ISSN: | 1945-7197 0021-972X |
| DOI: | 10.1210/jc.2009-0993 |
| Popis: | Background: Carney complex (CNC) is a familial multiple neoplasia syndrome frequently associated with primary pigmented nodular adrenocortical disease (PPNAD), a bilateral form of micronodular adrenal hyperplasia that leads to Cushing's syndrome (CS). Germline PRKAR1A mutations cause CNC and only rarely isolated PPNAD. Patients and Methods: PRKAR1A mutation analysis in two large families with CS and no other CNC manifestations demonstrated a M1V germline mutation; a total of 21 asymptomatic individuals were screened, and mutation carriers were evaluated for CNC. The mutation was expressed in vitro and functionally tested for its effects on protein kinase A function. Results: Presymptomatic testing identified five first-degree relatives who were M1V carriers and who were all diagnosed with subclinical, mild CS at ages ranging from 20-56 yr. There were no other signs of CNC. In a cell-free system, we detected a shorter compared with the wild-type type 1 alpha regulatory subunit of protein kinase A (PRKAR1A) protein (43 kDa). This was not identified in cell lines from the patients or in transfection experiments in HEK293 cells that showed no detectable PRKAR1A protein from the M1V-bearing constructs. In these cells, the mutant mRNA was expressed in a 1: 1 ratio. Conclusion: In two large families, the M1V PRKAR1A mutation resulted in a PPNAD-only phenotype with significant variability both in terms of age of onset and clinical severity. Expression studies showed a unique effect of this sequence change. This study has implications for genetic counseling of carriers of this PRKAR1A mutation and patients with CNC and PPNAD and for the study of PRKAR1A-related tumorigenesis. (J Clin Endocrinol Metab 95: 338-342, 2010) |
| Databáze: | OpenAIRE |
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