Molecular determinants and signaling effects of PKA RIα phase separation.

Spatiotemporal regulation of intracellular signaling molecules, such as the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), ensures proper cellular function. Liquid-liquid phase separation (LLPS) of the ubiquitous PKA regulatory subunit RIα promotes cAMP compartmentation and signaling specificity. However, the molecular determinants of RIα LLPS remain unclear. Here, we reveal that two separate dimerization interfaces, combined with the cAMP-induced unleashing of the PKA catalytic subunit (PKA-C) from the pseudosubstrate inhibitory sequence, drive RIα condensate formation in the cytosol of mammalian cells, which is antagonized by docking to A-kinase anchoring proteins. Strikingly, we find that the RIα pseudosubstrate region is critically involved in forming a non-canonical R:C complex, which recruits active PKA-C to RIα condensates to maintain low basal PKA activity in the cytosol. Our results suggest that RIα LLPS not only facilitates cAMP compartmentation but also spatially restrains active PKA-C, thus highlighting the functional versatility of biomolecular condensates in driving signaling specificity.

Dualistic Effects of PRKAR1A as a Potential Anticancer Target in Cancer Cells and Cancer-Derived Stem Cells.

The integration of innovative medical technologies and interdisciplinary collaboration could improve the treatment of cancer, a globally prevalent and often deadly disease. Despite recent advancements, current cancer therapies fail to specifically address recurrence and target cancer stem cells (CSCs), which contribute to relapse. In this study, we utilized three types of cancer cells, from which three types of CSCs were further derived, to conduct a proteomic analysis. Additionally, shared cell surface biomarkers were identified as potential targets for a comprehensive treatment strategy. The selected biomarkers were evaluated through short hairpin RNA treatment, which revealed contrasting functions in cancer cells and CSCs. Knockdown of the identified proteins revealed that they regulate the epithelial-mesenchymal transition (EMT) and stemness via the ERK signaling pathway. Resistance to anticancer agents was consequently reduced, ultimately enhancing the overall anticancer effects of the treatment. Additionally, the significance of these biomarkers in clinical patient outcomes was confirmed using bioinformatics. Our study suggests a novel cancer treatment strategy that addresses the limitations of current anticancer therapies.

14-3-3 interaction with phosphodiesterase 8A sustains PKA signaling and downregulates the MAPK pathway.

The cAMP/PKA and mitogen-activated protein kinase (MAPK) signaling cascade control many cellular processes and are highly regulated for optimal cellular responses upon external stimuli. Phosphodiesterase 8A (PDE8A) is an important regulator that inhibits signaling via cAMP-dependent PKA by hydrolyzing intracellular cAMP pool. Conversely, PDE8A activates the MAPK pathway by protecting CRAF/Raf1 kinase from PKA-mediated inhibitory phosphorylation at Ser259 residue, a binding site of scaffold protein 14-3-3. It still remains enigmatic as to how the cross-talk involving PDE8A regulation influences cAMP/PKA and MAPK signaling pathways. Here, we report that PDE8A interacts with 14-3-3ζ in both yeast and mammalian system, and this interaction is enhanced upon the activation of PKA, which phosphorylates PDE8A's Ser359 residue. Biophysical characterization of phospho-Ser359 peptide with 14-3-3ζ protein further supports their interaction. Strikingly, 14-3-3ζ reduces the catalytic activity of PDE8A, which upregulates the cAMP/PKA pathway while the MAPK pathway is downregulated. Moreover, 14-3-3ζ in complex with PDE8A and cAMP-bound regulatory subunit of PKA, RIα, delays the deactivation of PKA signaling. Our results define 14-3-3ζ as a molecular switch that operates signaling between cAMP/PKA and MAPK by associating with PDE8A.

Carney complex predisposes to breast cancer: prospective study of 50 women.

OBJECTIVE: Carney complex (CNC) is a rare genetic syndrome, mostly due to germline loss-of-function pathogenic variants in PRKAR1A. Carney complex includes pigmented skin lesions, cardiac myxomas, primary pigmented nodular adrenocortical dysplasia, and various breast benign tumors. DESIGN: The present study was designed to describe the characteristics of breast lesions in CNC patients and their association with other manifestations of CNC and PRKAR1A genotype. METHODS: A 3-year follow-up multicenter French prospective study of CNC patients included 50 women who were analyzed for CNC manifestations and particularly breast lesions, with breast imaging, genotyping, and hormonal settings. RESULTS: Among the 38 women with breast imaging, 14 (39%) had breast lesions, half of them bilateral. Ten women (26%) presented with benign lesions and six with breast carcinomas (16%): one had ductal carcinoma in situ at 54, and five had invasive cancer before 50 years old, whom one with contralateral breast cancer during follow-up. The occurrence of breast cancer was more frequent in women with PRKAR1A pathogenic variant odds ratio = 6.34 (1.63-17.91) than in general population of same age. The mean age at breast cancer diagnosis was 44.7 years old: 17 years younger than in the general population. Breast cancer patients had good prognosis factors. All breast carcinomas occurred in individuals with familial CNC and PRKAR1A pathogenic variants. Loss of heterozygosity at the PRKAR1A locus in the 2 invasive breast carcinomas analyzed suggested a driver role of this tumor suppressor gene. CONCLUSIONS: As CNC could predispose to breast carcinoma, an adequate screening strategy and follow-up should be discussed in affected women. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov NCT00668291.

Whole genome sequencing resolves 10 years diagnostic odyssey in familiar myxoma.

Carney complex (CNC) is an ultrarare disorder causing cutaneous and cardiac myxomas, primary pigmented nodular adrenocortical disease, hypophyseal adenoma, and gonadal tumours. Genetic alterations are often missed under routine genetic testing. Pathogenic variants in PRKAR1A are identified in most cases, while large exonic or chromosomal deletions have only been reported in a few cases. Our aim was to identify the causal genetic alteration in our kindred with a clinical diagnosis of CNC and prove its pathogenic role by functional investigation. Targeted testing of PRKAR1A gene, whole exome and whole genome sequencing (WGS) were performed in the proband, one clinically affected and one unaffected relative. WGS identified a novel, large, 10,662 bp (10.6 kbp; LRG_514t1:c.-10403_-7 + 265del; hg19, chr17:g.66498293_66508954del) deletion in the promoter of PRKAR1A in heterozygous form in the affected family members. The exact breakpoints and the increased enzyme activity in deletion carriers compared to wild type carrier were proved. Segregation analysis and functional evaluation of PKA activity confirmed the pathogenic role of this alteration. A novel deletion upstream of the PRKAR1A gene was proved to be the cause of CNC. Our study underlines the need for WGS in molecular genetic testing of patients with monogenic disorders where conventional genetic analysis fails.

Crosstalk between KIF1C and PRKAR1A in left atrial myxoma.

Cardiac myxoma (CM) is the most common benign cardiac tumor, and most CMs are left atrial myxomas (LAMs). Six variations of KIF1C, c.899 A > T, c.772 T > G, c.352 A > T, c.2895 C > T, c.3049 G > A, and c.*442_*443dup in left atrial myxoma tissues are identified by whole-exome sequencing (WES) and Sanger sequencing. RNA-seq and function experiments show the reduction of the expression of KIF1C and PRKAR1A caused by rare variations of KIF1C. KIF1C is observed to be located in the nucleus, bind to the promoter region of PRKAR1A, and regulate its transcription. Reduction of KIF1C decreases PRKAR1A expression and activates the PKA, which causes an increase in ERK1/2 phosphorylation and SRC-mediated STAT3 activation, a reduction of CDH1, TP53, CDKN1A, and BAX, and eventually promotes tumor formation both in vitro and in vivo. The results suggest that inhibition of KIF1C promotes the pathogenesis of LAM through positive feedback formed by the crosstalk between KIF1C and PRKAR1A.

Carney complex- why thorough medical history taking is so important - report of three cases and review of the literature.

PURPOSE: To present a new case series and to review the literature on Carney complex (CNC) with an emphasis on highlighting key clinical features of the disease and pointing out possibilities of shortening the diagnostic process. METHOD: Searches of PubMed, identifying relevant reports up to April 2022. RESULTS: CNC is a rare, autosomally dominant inherited neoplasia -endocrinopathy syndrome with high clinical variability, even among members of the same family. Data on length of diagnostic process are scarce with numerous case series reporting a diagnostic delay of decades. Suggestions to shorten the diagnostic process includes awareness of the multi-faceted clinical presentations of CNC, thorough history taking of index patients and family members and awareness of diagnostic pitfalls. Importantly, unusual symptom combinations should alert the clinician to suspect a rare endocrinopathy syndrome such as CNC. Already present and coming on the horizon are databases and novel phenotyping technologies that will aid endocrinologists in their quest for timely diagnosis. CONCLUSION: In this review, we examine the current state of knowledge in CNC and suggest avenues for shortening the diagnostic journey for the afflicted patients.

Somatic Mutation of PRKAR1A in Four Cases of Sporadic Cardiac Myxoma.

BACKGROUND: Inactivating mutations of the protein kinase A regulatory subunit 1 alpha (PRKAR1A) gene have been reported in familial cardiac myxoma. However, the role of PRKAR1A mutation in sporadic cardiac myxoma remains unknown. METHODS: Targeted next-generation sequencing (NGS) was performed to identify mutations with the PRKAR1A gene in seven cases of sporadic cardiac myxomas. Sanger sequencing of DNA from cardiac myxoma specimens and matched peripheral blood samples was performed to verify the identified mutations. RESULTS: Targeted NGS of myxoma DNA revealed 232 single nucleotide variants in 141 genes and 38 insertion-deletion mutations in 13 genes. Six PRKAR1A mutations were identified in four of the seven cardiac myxoma cases, and thus, the PRKAR1A inactivating mutation rate was 57.2% (4/7, 95% CI=0.44-0.58, P<0.05). The PRKAR1A variants identified by Sanger sequencing analysis were consistent with those from the NGS analysis for the four myxoma specimens. All of the pathogenic PRKAR1A mutations led to premature termination of PRKAR1A, except for one synonymous mutation. Moreover, none of the nonsense and missense mutations found in the myxoma specimens were found in the matched peripheral blood samples. CONCLUSION: Pathogenic mutations of the PRKAR1A gene were identified in tumor specimens from four cases of sporadic cardiac myxoma, and the absence of these mutations in peripheral blood samples demonstrated that they were somatic mutations.

Unusual Findings in a Patient With Carney Complex due to a Novel PRKAR1A Mutation.

BACKGROUND/AIM: Carney complex (CNC) is a rare autosomal dominant tumor-predisposition syndrome with variable expression. Its main features are pigmentary skin lesions, soft-tissue myxomas, and endocrine overactivity or tumors. There is occasional overlap with other syndromes, and oligosymptomatic cases may escape diagnosis. This report describes the long journey of a patient until the diagnosis of CNC was finally made after a thorough diagnostic workup. CASE REPORT: The female patient was referred for treatment of a subcutaneous tumor of the lower abdomen. Medical reports detailed previous excisions of fibroma, neurofibroma and myxoma, and a malignant tumor of the cerebellopontine angle. The resected subcutaneous tumor was a myxoma. The identification of a previously unknown frameshift mutation in the gene for protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) in the patient confirmed the diagnosis of CNC. CONCLUSION: Patients with CNC may have highly variable clinical findings. Some rare lesions in CNC are more commonly recorded in other syndromes, making early diagnosis difficult in some cases. Genetic testing greatly facilitates diagnosis.

Acinar cell carcinoma with PRKAR1A and PTEN alterations and paraneoplastic panniculitis.

Pancreatic acinar cell carcinoma is a rare type of pancreatic malignancy, which can be confused with pancreatic neuroendocrine neoplasm. Here, we describe a woman in her 80s who presented with abdominal pain and bilateral lower extremity panniculitis. She underwent surgery for a presumed diagnosis of neuroendocrine tumour with PTEN and PRKAR1A alterations; 19 months, later, a recurrence of her pancreatic malignancy was discovered. The patient underwent repeat resection and this time immunohistochemical staining confirmed the diagnosis of acinar cell carcinoma. Staining for acinar cell carcinoma should be prompted based on clinical suspicion in context of PTEN or PRKAR1A mutation when appropriate.

Association between subclinical hyperthyroidism and a PRKAR1A gene variant in Carney complex patients: A case report and systematic review.

Background and Objectives: It is currently controversial whether subclinical hyperthyroidism is associated with PRKAR1A gene variants. We describe a man with subclinical hyperthyroidism and a PRKAR1A gene variant who was diagnosed with Carney complex (CNC), and we performed a systematic review of published studies to assess the association between PRKAR1A gene variants and the risk of subclinical hyperthyroidism. Design and Methods: The PubMed, EMBASE, OVID, Science Direct, and gray literature electronic databases were searched for articles published from January 2002 to May 2021 using predefined keywords and inclusion and exclusion criteria. Data on thyroid function from selected studies were extracted and analyzed. Results: We identified a CNC patient with a subclinical hyperthyroidism phenotype combined with multiple components and genetic sequenced data. In a subsequent systematic review, twenty selected studies (14 case studies and 6 series studies) enrolling 23 individuals were included in the final analysis. The patient's thyroid function data were qualitative in 11 cases and quantitative in 12 cases. The prevalence of subclinical hyperthyroidism in the CNC patients with a PRKAR1A gene variant, including our patient, was markedly higher than that in the normal population (12.5% vs. 2%). Conclusions: The findings of this systematic review provide helpful evidence that PRKAR1A gene variants and subclinical hyperthyroidism are related and suggest that subclinical hyperthyroidism may be a neglected phenotype of PRKAR1A gene variants and a novel component of CNC patients. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42021197655.

A Novel Missense PRKAR1A Variant Causes Carney Complex.

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.

STK25 inhibits PKA signaling by phosphorylating PRKAR1A.

In the heart, protein kinase A (PKA) is critical for activating calcium handling and sarcomeric proteins in response to beta-adrenergic stimulation leading to increased myocardial contractility and performance. The catalytic activity of PKA is tightly regulated by regulatory subunits that inhibit the catalytic subunit until released by cAMP binding. Phosphorylation of type II regulatory subunits promotes PKA activation; however, the role of phosphorylation in type I regulatory subunits remain uncertain. Here, we utilize human induced pluripotent stem cell cardiomyocytes (iPSC-CMs) to identify STK25 as a kinase of the type Iα regulatory subunit PRKAR1A. Phosphorylation of PRKAR1A leads to inhibition of PKA kinase activity and increased binding to the catalytic subunit in the presence of cAMP. Stk25 knockout in mice diminishes Prkar1a phosphorylation, increases Pka activity, and augments contractile response to beta-adrenergic stimulation. Together, these data support STK25 as a negative regulator of PKA signaling through phosphorylation of PRKAR1A.

Phenotypic Variability in a Family with Carney Complex Accompanied by a Novel Mutation Involving PRKAR1A.

Carney complex is a rare, autosomal dominant disease accompanied by multiple endocrine neoplastic syndromes. Mutations in the PRKAR1A gene have recently been reported as a cause of Carney complex, but genotype-phenotype correlations vary widely. A 15-year-old Japanese man (Case 1) with short stature visited our hospital with suspected Cushing's syndrome. Biochemical investigations suggested corticotropin-independent Cushing's syndrome. Computed tomography revealed multiple bilateral adrenal tumors, and a two-staged partial adrenalectomy was performed. Pathological findings revealed primary pigmented nodular adrenocortical disease (PPNAD). The patient also exhibited distinctive spotty skin pigmentation. Based on these features, the patient was diagnosed as Carney complex. Cascade screening of family members was performed, and the mother (Case 2) and elder brother (Case 3) were diagnosed as Carney complex. Case 2 showed cardiac myxoma, acromegaly, spotty skin pigmentation, and mammary myxoid fibroadenoma. Case 3 exhibited gigantism, spotty skin pigmentation, and thyroid nodules. Target gene testing in Case 1 and 2 revealed the same novel mutation in PRKAR1A gene (c.503G>T, p.Gly168Val). This mutation was predicted as a pathogenic variant by multiple in silico analyses. Here, we present a family of Carney complex cases with a novel PRKAR1A pathogenic variant exhibiting varied clinical phenotypes within each case. In these cases, some specific phenotypes of Carney complex, such as pigmentary disorders, myxomas, and PPNAD are important as clues for diagnosis and prognostic factors. Clinicians should consider further examination in patients with Carney complex-specific phenotypes.

Next-Generation Sequencing Reveals a New Class of Melanocytic Neoplasms With Hybrid Genomic Features of PEM Including Protein Kinase R 1 Alpha Gene Inactivation and Spitz Tumor-Defining Protein Kinase Fusions.

BACKGROUND: Pigmented epithelioid melanocytoma (PEM) is a subtype of melanocytic tumor with frequent involvement of the sentinel lymph node but rare distant metastasis. Rendering a diagnosis and prognosis based on histology can be challenging. Recent genomic studies identified 2 molecular variants of PEM. One variant is characterized by the activation of the mitogen-activated protein kinase pathway and inactivation of the PRKAR1a gene. The other is associated with genomic fusions involving the protein kinase C ( PRKC ) gene family. OBJECTIVE: We investigated the molecular and clinicopathologic features of previously unreported PEM cases to improve tumor classification and report new classes of PEM. METHODS: Next-generation sequencing and histomorphologic assessment was performed on 13 PEM cases. RESULTS: We identified 2 novel PEM classes. Three cases harbored PRKAR1a inactivation and genomic fusions ( ALK , NTRK , and MAP3K8 ). These tumors had overlapping histologic features with pigmented Spitz neoplasms. Three cases had genomic fusions involving PRKCB . These cases had overlapping features with PRKCA fusions but, in 2 cases, had a notable spindle cell component. LIMITATIONS: The overall sample size and amount of clinical follow-up is limited, leaving some uncertainty regarding the expected clinical course of these novel cases. CONCLUSIONS: PRKAR1a-inactivated/Spitz fusion-associated PEMs and PRKCB fusion-associated PEMs represent 2 new molecular classes of PEM.

Steroidogenic Factor-1 Lineage Origin of Skin Lesions in Carney Complex Syndrome.

Carney complex is a rare familial multineoplastic syndrome predisposing to endocrine and nonendocrine tumors due to inactivating mutations of PRKAR1A, leading to perturbations of the cAMP‒protein kinase A signaling pathway. Skin lesions are the most common manifestation of Carney complex, including lentigines, blue nevi, and cutaneous myxomas in unusual locations such as oral and genital mucosa. Unlike endocrine disorders, the pathogenesis of skin lesions remains unexplained. In this study, we show that embryonic invalidation of the Prkar1a gene in steroidogenic factor-1‒expressing cells leads to the development of familial skin pigmentation alterations, reminiscent of those in patients with Carney complex. Immunohistological and molecular analyses, coupled with genetic monitoring of recombinant cell lineages in mouse skin, suggest that familial lentiginosis and myxomas occur in skin areas specifically enriched in dermal melanocytes. In lentigines- and blue nevi‒prone areas from mutant mice and patients, Prkar1a/PRKAR1A invalidation occurs in a subset of dermal fibroblasts capable of inducing, under the influence of protein kinase A signaling, the production of promelanogenic EDN3 and hepatocyte GF signals. Our model strongly suggests that the origin of the typical Carney complex cutaneous lesions is the result of noncell-autonomous promelanogenic activity of a dermal fibroblast population sharing a community of origin with steroidogenic factor-1 lineage.

PRKAR1A and SDCBP Serve as Potential Predictors of Heart Failure Following Acute Myocardial Infarction.

Background and Objectives: Early diagnosis of patients with acute myocardial infarction (AMI) who are at a high risk of heart failure (HF) progression remains controversial. This study aimed at identifying new predictive biomarkers of post-AMI HF and at revealing the pathogenesis of HF involving these marker genes. Methods and Results: A transcriptomic dataset of whole blood cells from AMI patients with HF progression (post-AMI HF, n = 16) and without progression (post-AMI non-HF, n = 16) was analyzed using the weighted gene co-expression network analysis (WGCNA). The results indicated that one module consisting of 720 hub genes was significantly correlated with post-AMI HF. The hub genes were validated in another transcriptomic dataset of peripheral blood mononuclear cells (post-AMI HF, n = 9; post-AMI non-HF, n = 8). PRKAR1A, SDCBP, SPRED2, and VAMP3 were upregulated in the two datasets. Based on a single-cell RNA sequencing dataset of leukocytes from heart tissues of normal and infarcted mice, PRKAR1A was further verified to be upregulated in monocytes/macrophages on day 2, while SDCBP was highly expressed in neutrophils on day 2 and in monocytes/macrophages on day 3 after AMI. Cell-cell communication analysis via the "CellChat" package showed that, based on the interaction of ligand-receptor (L-R) pairs, there were increased autocrine/paracrine cross-talk networks of monocytes/macrophages and neutrophils in the acute stage of MI. Functional enrichment analysis of the abovementioned L-R genes together with PRKAR1A and SDCBP performed through the Metascape platform suggested that PRKAR1A and SDCBP were mainly involved in inflammation, apoptosis, and angiogenesis. The receiver operating characteristic (ROC) curve analysis demonstrated that PRKAR1A and SDCBP, as well as their combination, had a promising prognostic value in the identification of AMI patients who were at a high risk of HF progression. Conclusion: This study identified that PRKAR1A and SDCBP may serve as novel biomarkers for the early diagnosis of post-AMI HF and also revealed their potentially regulatory mechanism during HF progression.

Attempting to Solve the Pigmented Epithelioid Melanocytoma (PEM) Conundrum: PRKAR1A Inactivation Can Occur in Different Genetic Backgrounds (Common, Blue, and Spitz Subgroups) With Variation in Their Clinicopathologic Characteristics.

Pigmented epithelioid melanocytoma is a rare cutaneous melanocytic proliferation considered high-grade melanocytoma in the 2018 WHO Classification of Skin Tumors. Little has been reported about the associated genetic drivers in addition to BRAF and MAP2K1 mutations or PRKCA gene fusions. Here, we present a series of 21 cases of PRKAR1A -inactivated melanocytic tumors in which we could assess the associated genetic background. We identified 9 different driver genes related to the common, Spitz, blue nevi, and PRKC -fused groups. Nine cases were associated with a canonical BRAF p.V600E mutation, a hallmark of the common nevus group. They occurred mainly in young adults. All were combined (biphenotypic) cases with a variable proportion of compound nevus. The pigmented epithelioid melanocytoma component was made of thin fascicules or isolated epithelioid cells covered by a dense hyperpigmented melanophage background and was predominantly located in the upper dermis. One such case was malignant. Six cases were associated with Spitz-related genetic anomalies ranging from HRAS or MAP2K1 mutations to gene fusions involving MAP3K8 , MAP3K3 , and RET . They occurred mainly in children and young adults. Morphologically, they showed large confluent junctional nests in a hyperplastic epidermis and a fascicular dermal component of spindled and epithelioid melanocytes with a frequent wedged silhouette. Intravascular invasion was observed in 4/6 cases. Five cases were associated with canonical mutations of the blue nevus group with 4 CYSLTR2 p.L129Q and 1 GNAQ p.Q209L mutations. They were removed mainly in adults and showed a frequent junctional component with epidermal hyperplasia. The dermal component showed dense fascicules of spindled and epithelioid melanocytes predominating over melanophages. One case occurred in a PRKCA -fused tumor in an adolescent with classic morphologic features. These results could potentially shift the concept of PRKAR1A -inactivated melanocytoma, changing from a rather unified model to a more complex one, including genetic subgroup variations with clinical and morphologic specificities. The genetic background of PRKAR1A -inactivated melanocytic tumors should be systematically explored to better understand the extent and clinical behavior of these complex lesions.

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

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.