Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

CNC is genetically and clinically heterogeneous. Certain tumors are more frequent, with specific mutations providing some genotype-phenotype correlation for PRKAR1A mutations.

• Authors: Jérôme Bertherat, Anélia Horvath, Lionel Groussin, Sophie Grabar, Sosipatros Boikos, Laure Cazabat, Rosella Libe, Fernande René-Corail, Sotirios Stergiopoulos, Isabelle Bourdeau, Thalia Bei, Eric Clauser, Alain Calender, Lawrence S Kirschner, Xavier Bertagna, J Aidan Carney, Constantine A Stratakis
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 94 Issue 6 Pg. 2085-91 (Jun 2009) ISSN: 1945-7197 [Electronic] United States
• PMID: 19293268 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic AMP-Dependent Protein Kinase RIalpha Subunit

Topics

• Adolescent
• Adrenal Cortex Diseases (complications, genetics)
• Adult
• Aged
• Aged, 80 and over
• Child
• Child, Preschool
• Cyclic AMP-Dependent Protein Kinase RIalpha Subunit (genetics)
• DNA Mutational Analysis
• Female
• Genotype
• Humans
• Infant
• Male
• Middle Aged
• Mutation (physiology)
• Myxoma (complications, genetics)
• Phenotype
• Young Adult