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.

Figure 1

Age of diagnosis of PPNAD. A, Age of diagnosis of PPNAD for all the patients. The estimated median age of diagnosis was 34 yr (IQR, 19–60). B, Age of diagnosis of PPNAD by gender (females in red, n = 221 patients, of whom 150 were diagnosed with PPNAD; males in black, n = 152 patients, of whom 62 were diagnosed with PPNAD).

Figure 2

Mutations and large deletions of the PRKAR1A gene. Gene localization of 80 PRKAR1A mutations or large deletions found in 258 patients with PRKAR1A genetic defects; mutations are marked below the schematic representation of the PRKAR1A gene that contains 11 exons. A, Mutations or deletions leading to a frameshift (green) or mutations creating a missense substitutions (blue). B, Mutations leading to nonsense changes (pink) or mutations or deletions altering splice sites (yellow).

Figure 3

Age of diagnosis of cardiac myxoma, thyroid tumor, PPNAD, and LCCSCT according to PRKAR1A genotype. The figure shows the estimated age of diagnosis in patients without (red line, n = 95 patients) or with PRKAR1A germline mutation (dotted black line, n = 258 patients), with the respective P value of the log-rank test comparing the two groups. A, Cardiac myxoma: for patients with a PRKAR1A mutation, the estimated median age of diagnosis of the first tumor was 45 yr (IQR, 30–78). B, Thyroid tumors: for patients with a PRKAR1A mutation, the estimated median age of diagnosis of the first thyroid tumor was 69 yr (IQR, 40-NR). C, PPNAD: for patients with a PRKAR1A mutation, the estimated median age of diagnosis of PPNAD was 35 yr (IQR, 22–60). D, LCCSCT: for male patients with a PRKAR1A mutation, the estimated median age of diagnosis of LCCSCT was 46 yr (IQR, 22–69).