Endocrinol Metab (Seoul). 2022;37(5):810-815.

A Novel Missense PRKAR1A Variant Causes Carney Complex.

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제1저자 김보람, 장한나 · 교신저자 성문우, 김정희

PMID 36193716 PMC9633213 DOI 10.3803/EnM.2022.1544 IF 5.1 내분비대사내과

소속 (6)

Department of Laboratory Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Pituitary Center, Seoul National University Hospital, Seoul, Korea.
Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Abstract

The Carney complex (CNC) is an autosomal dominant disorder characterized by endocrine and nonendocrine tumors. Loss-of-function variants of protein kinase A regulatory subunit 1 alpha (PRKAR1A) are common causes of CNC. Here, we present the case of a patient with CNC with a novel PRKAR1A missense variant. A 21-year-old woman was diagnosed with CNC secondary to acromegaly and adrenal Cushing syndrome. Genetic analysis revealed a novel missense heterozygous variant of PRKAR1A (c.176A>T). Her relatives, suspected of having CNC, also carried the same variant. RNA analysis revealed that this variant led to nonsense-mediated mRNA decay. In vitro functional analysis of the variant confirmed its role in increasing protein kinase A activity and cyclic adenosine monophosphate levels. This study broadens our understanding of the genetic spectrum of CNC. We suggest that PRKAR1A genetic testing and counseling be recommended for patients with CNC and their families.

Keywords

Carney complexGenetic counselingMissense mutationPRKAR1AVariant

Figures

**Fig. 1.** The patient’s adrenal gland. (A) Adrenal computed tomography was performed as cortisol level was elevated in the examination, considering secondary hypertension. Adrenal computed tomography revealed multiple small nodules in both the adrenal glands (arrows). (B) Pigmented micronodules were observed throughout the cortex of the adrenal gland in the patient who underwent adrenalectomy (arrows).

**Fig. 2.** The patient’s pedigree analysis, sequencing analysis of protein kinase A regulatory subunit 1 alpha (*PRKAR1A*), and the protein kinase A (PKA) activity and cyclic adenosine monophosphate (cAMP) levels in *PRKAR1A* mutants. (A) Family tree of the patient diagnosed with the Carney complex. The patient’s mother had acromegaly and adrenal Cushing’s syndrome and died of colon cancer. Both her uncles were treated for acromegaly. Genetic testing confirmed the same variant in all of her mother’s brothers, one sister, and four symptomatic cousins (*). Two cousins (III.3 and III.8) are asymptomatic carriers. Family members who underwent genetic testing for the variant of *PRKAR1A*. (B) DNA sequencing result showing a novel missense variant, NM_002734.5(*PRKAR1A*): c.176A>T. (C) RNA sequencing analysis showing the absence of the variant. (D) Relative PKA activity was significantly higher in both a previously known mutant (c.491_492del) and the new mutant found in the patient of this study (c.176A>T) than in the wild type (WT), and there was no significant difference in the relative PKA activity between the c.491_492del and c.176A>T mutants. (E) Relative cAMP level in both the c.491_492del and c.176A>T mutants was significantly higher than that in the WT. PRKACA, protein kinase cAMP-activated catalytic subunit alpha. aP<0.001.

그림 출처: PubMed Central 공개 논문 (PMC9633213)

Conflict of interest statement

CONFLICTS OF INTEREST . No potential conflict of interest relevant to this article was reported.

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