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Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families.

ABSTRACT: 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 1alpha 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.

SUBMITTER: Pereira AM

PROVIDER: S-EPMC2805491 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families.

Pereira Alberto M AM Hes Frederik J FJ Horvath Anelia A Woortman Sanne S Greene Elizabeth E Bimpaki Eirini E Alatsatianos Anton A Boikos Sosipatros S Smit Johannes W JW Romijn Johannes A JA Nesterova Maria M Stratakis Constantine A CA

The Journal of clinical endocrinology and metabolism 20091113 1

<h4>Background</h4>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.<h4>Patients and methods</h4>PRKAR1A mutation analysis in two large families with CS and no other CNC manifestations demonstrated a M1V germline mutation; a total of 21 asym ...[more]

PMID: 19915019

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Project description:ContextMost tumors in Carney complex (CNC) are benign, including primary pigmented nodular adrenocortical disease (PPNAD), the main endocrine tumor in CNC. Adrenocortical cancer (AC) has never been observed in the syndrome. Herein, we describe a large Azorean family with CNC caused by a point mutation in the PRKAR1A gene coding for type 1-α (RIα) regulatory subunit of the cAMP-dependent protein kinase A, in which the index patient presented with AC.ObjectiveWe studied the genotype-phenotype correlation in CNC.Design and settingWe reported on case series and in vitro testing of the PRKAR1A mutation in a tertiary care referral center.PatientsTwenty-two members of a family were investigated for Cushing syndrome and other CNC components; their DNA was sequenced for PRKAR1A mutations.ResultsCushing syndrome due to PPNAD occurred in four patients, including the proposita who presented with AC and three who had Cushing syndrome and/or PPNAD. Lentigines were found in six additional patients who did not have PPNAD. A base substitution (c.439A>G/p.S147G) in PRKAR1A was identified in the proposita, in the three others with PPNAD, in the proposita's twin daughters who had lentigines but no evidence of hypercortisolism, and in five other family members, including one without lentigines or evidence of hypercortisolism. Unlike in other RIα defects, loss of heterozygosity was not observed in AC. The S147G mutation was compared to other expressed PRKAR1A mutations; it led to decreased cAMP and catalytic subunit binding by RIα and increased protein kinase A activity in vitro.ConclusionsIn a large family with CNC, one amino acid substitution caused a spectrum of adrenal disease that ranged from lack of manifestations to cancer. PPNAD and AC were the only manifestations of CNC in these patients, in addition to lentigines. These data have implications for counseling patients with CNC and are significant in documenting the first case of AC in the context of PPNAD.

Dataset Information

Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families.

Publications

Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families.

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