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- Title
Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes.
- Authors
Bertherat, Jérôme; Horvath, Anélia; Groussin, Lionel; Grabar, Sophie; Boikos, Sosipatros; Cazabat, Laure; Libe, Rosella; René-Corail, Fernande; Stergiopoulos, Sotirios; Bourdeau, Isabelle; Bei, Thalia; Clauser, Eric; Calender, Alain; Kirschner, Lawrence S; Bertagna, Xavier; Carney, J Aidan; Stratakis, Constantine A
- Abstract
<bold>Background: </bold>The "complex of myxomas, spotty skin pigmentation, and endocrine overactivity," or "Carney complex" (CNC), is caused by inactivating mutations of the regulatory subunit type 1A of the cAMP-dependent protein kinase (PRKAR1A) gene and as yet unknown defect(s) in other gene(s). Delineation of a genotype-phenotype correlation for CNC patients is essential for understanding PRKAR1A function and providing counseling and preventive care.<bold>Methods: </bold>A transatlantic consortium studied the molecular genotype and clinical phenotype of 353 patients (221 females and 132 males, age 34 +/- 19 yr) who carried a germline PRKAR1A mutation or were diagnosed with CNC and/or primary pigmented nodular adrenocortical disease.<bold>Results: </bold>A total of 258 patients (73%) carried 80 different PRKAR1A mutations; 114 (62%) of the index cases had a PRKAR1A mutation. Most PRKAR1A mutations (82%) led to lack of detectable mutant protein (nonexpressed mutations) because of nonsense mRNA mediated decay. Patients with a PRKAR1A mutation were more likely to have pigmented skin lesions, myxomas, and thyroid and gonadal tumors; they also presented earlier with these tumors. Primary pigmented nodular adrenocortical disease occurred earlier, was more frequent in females, and was the only manifestation of CNC with a gender predilection. Mutations located in exons were more often associated with acromegaly, myxomas, lentigines, and schwannomas, whereas the frequent c.491-492delTG mutation was commonly associated with lentigines, cardiac myxomas, and thyroid tumors. Overall, nonexpressed PRKAR1A mutations were associated with less severe disease.<bold>Conclusion: </bold>CNC is genetically and clinically heterogeneous. Certain tumors are more frequent, with specific mutations providing some genotype-phenotype correlation for PRKAR1A mutations.
- Subjects
ADRENAL diseases; COMPARATIVE studies; RESEARCH methodology; MEDICAL cooperation; GENETIC mutation; MYXOMA; PHOSPHOTRANSFERASES; RESEARCH; RESEARCH funding; PHENOTYPES; EVALUATION research; SEQUENCE analysis; GENOTYPES; DISEASE complications
- Publication
Journal of Clinical Endocrinology & Metabolism, 2009, Vol 94, Issue 6, p2085
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2008-2333