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A novel 8.57-kb deletion of the upstream region of PRKAR1A in a family with Carney complex.

ABSTRACT: Carney complex (CNC) is a rare hereditary syndrome that involves endocrine dysfunction and the development of various types of tumors. Chromosome 2p16 and PRKAR1A on chromosome 17 are known susceptibility loci for CNC. Here we report a mother and son with CNC caused by an 8.57-kb deletion involving the transcription start site and non-coding exon 1 of PRKAR1A. The proband is a 28-year-old male with bilateral large-cell calcified Sertoli cell testicular tumors and pituitary adenoma. Comprehensive genomic profiling for cancer mutations using Foundation One CDx failed to detect any mutations in PRKAR1A in DNA from the testicular tumor. Single-nucleotide polymorphism array analysis of the proband's genomic DNA revealed a large deletion in the 5' region of PRKAR1A. Genomic walking further delineated the region an 8.57-kb deletion. A 1.68-kb DNA fragment encompassed by the deleted region showed strong promoter activity in a NanoLuc luciferase reporter assay. The patient's mother, who is suffering from recurrent cardiac myxoma, a critical sign for CNC, carried an identical deletion. The 8.57-kb deleted region is a novel lesion for CNC and will facilitate molecular diagnosis of the disease.

SUBMITTER: Ito S

PROVIDER: S-EPMC8922967 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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A novel 8.57-kb deletion of the upstream region of PRKAR1A in a family with Carney complex.

Ito Shin S Hashimoto Aya A Yamaguchi Kazunori K Kawamura Sadafumi S Myoen Shingo S Ogawa Maki M Sato Ikuro I Minato Takamichi T Miyabe Shingo S Nakazato Akira A Fujii Keitaro K Mochizuki Mai M Fujimori Haruna H Tamai Keiichi K Niihori Tetsuya T Aoki Yoko Y Sugawara Akira A Sasano Hironobu H Shima Hiroshi H Yasuda Jun J

Molecular genetics & genomic medicine 20220206 3

Carney complex (CNC) is a rare hereditary syndrome that involves endocrine dysfunction and the development of various types of tumors. Chromosome 2p16 and PRKAR1A on chromosome 17 are known susceptibility loci for CNC. Here we report a mother and son with CNC caused by an 8.57-kb deletion involving the transcription start site and non-coding exon 1 of PRKAR1A. The proband is a 28-year-old male with bilateral large-cell calcified Sertoli cell testicular tumors and pituitary adenoma. Comprehensive ...[more]

PMID: 35128829

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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

A novel 8.57-kb deletion of the upstream region of PRKAR1A in a family with Carney complex.

Publications

A novel 8.57-kb deletion of the upstream region of PRKAR1A in a family with Carney complex.

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