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https://www.readbyqxmd.com/read/28522647/prkar1a-mutation-causing-pituitary-dependent-cushing-disease-in-a-patient-with-carney-complex
#1
Florian W Kiefer, Yvonne Winhofer, Donato Iacovazzo, Marta Korbonits, Stefan Wolfsberger, Engelbert Knosp, Franz Trautinger, Romana Höftberger, Michael Krebs, Anton Luger, Alois Gessl
CONTEXT: Carney complex (CNC) is an autosomal dominant condition caused, in most cases, by an inactivating mutation of the PRKAR1A gene, which encodes for the type 1 alpha regulatory subunit of protein kinase A. CNC is characterized by the occurrence of endocrine overactivity, myxomas and typical skin manifestations. Cushing syndrome due to primary pigmented nodular adrenocortical disease (PPNAD) is the most frequent endocrine disease observed in CNC. CASE DESCRIPTION: Here we describe the first case of a patient with CNC and adrenocorticotropic hormone (ACTH)-dependent Cushing disease due to a pituitary corticotroph adenoma...
May 18, 2017: European Journal of Endocrinology
https://www.readbyqxmd.com/read/28515031/phenotypic-variability-in-a-family-with-acrodysostosis-type-2-caused-by-a-novel-pde4d-mutation-affecting-the-serine-target-of-pka-phosphorylation
#2
Julia Hoppmann, Julia Gesing, Caroline Silve, Chrystel Leroy, Astrid Bertsche, Franz Wolfgang Hirsch, Wieland Kiess, Roland Pfäffle, Volker Schuster
BACKGROUND: Acrodysostosis is a very rare congenital multisystem condition characterized by skeletal dysplasia with severe brachydactyly, midfacial hypoplasia, and short stature, varying degrees of intellectual disability, and possible resistance to multiple G protein-coupled receptor signalling hormones. Two distinct subtypes are differentiated: acrodysostosis type 1 resulting from defects in PRKAR1A and acrodysostosis type 2 caused by mutations in PDE4D. Most cases are sporadic. OBJECTIVE: We report on a rare multigenerational familial case of acrodysostosis type 2 due to a novel autosomal dominantly inherited PDE4D mutation...
May 17, 2017: Journal of Clinical Research in Pediatric Endocrinology
https://www.readbyqxmd.com/read/28513873/myxoid-fibroadenomas-differ-from-conventional-fibroadenomas-a-hypothesis-generating-study
#3
John R Lozada, Kathleen A Burke, Aoife Maguire, Fresia Pareja, Raymond S Lim, Jisun Kim, Rodrigo Gularte-Merida, Melissa P Murray, Edi Brogi, Britta Weigelt, Jorge S Reis-Filho, Felipe C Geyer
AIMS: Breast myxoid fibroadenomas (MFAs) are characterized by a distinctive hypocellular myxoid stroma, and occur sporadically or in the context of Carney Complex, an inheritable condition caused by PRKAR1A inactivating germline mutations. Conventional fibroadenomas (FAs) are underpinned by recurrent MED12 mutations in the stromal components of the lesions. We sought to investigate the genomic landscape of MFAs and compare it to that of conventional FAs. METHODS AND RESULTS: Eleven MFAs from patients without clinical and/or genetic evidence of Carney Complex were retrieved...
May 17, 2017: Histopathology
https://www.readbyqxmd.com/read/28488625/genetics-of-pituitary-adenomas
#4
Mario Shaid, Márta Korbonits
Clinically relevant pituitary tumors presenting with altered hormonal secretion or mass effect represent a significant proportion of patients in endocrinology clinics. However, in recent years, these patients are also referred to clinical genetic services due to possible germline mutations causing syndromic or isolated pituitary adenomas. While somatic mutations have been identified in GNAS, USB8, PIK3CA, GPR101 and rarely in RAS, germline mutations have been identified in MEN1, cyclin dependent kinase inhibitor genes, AIP, DICER1, PRKAR1A, PRKACA, SDH genes and GPR101...
May 2017: Neurology India
https://www.readbyqxmd.com/read/28369983/microinsertions-in-prkaca-cause-activation-of-the-protein-kinase-a-pathway-in-cardiac-myxoma
#5
I-Ching Tseng, Wei-Ju Huang, Yu-Ling Jhuang, Ya-Yun Chang, Hung-Pin Hsu, Yung-Ming Jeng
Cardiac myxoma is the most common cardiac tumour. Most lesions occur sporadically, but occasional lesions develop in patients with Carney complex, a syndrome characterised by cardiac myxoma, spotty pigmentation, and endocrine overactivity. Two-thirds of patients with Carney complex harbour germline mutations in PRKAR1A, which encodes the type I regulatory subunit of protein kinase A (PKA). Most studies have not found a mutation in PRKAR1A in sporadic cardiac myxoma cases. Recent studies identified frequent mutation in PRKACA, the catalytic subunit of PKA, in cortisol-secreting adrenocortical adenoma cases...
March 28, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28220018/germline-variants-in-familial-pituitary-tumour-syndrome-genes-are-common-in-young-patients-and-families-with-additional-endocrine-tumours
#6
Sunita M C De Sousa, Mark J McCabe, Kathy Wu, Tony Roscioli, Velimir Gayevskiy, Katelyn Brook, Lesley Rawlings, Hamish S Scott, Tanya J Thompson, Peter Earls, Anthony J Gill, Mark J Cowley, Marcel E Dinger, Ann I McCormack
OBJECTIVE: Familial pituitary tumour syndromes (FPTS) account for 5% of pituitary adenomas. Multi-gene analysis via next-generation sequencing (NGS) may unveil greater prevalence and inform clinical care. We aimed to identify germline variants in selected patients with pituitary adenomas using a targeted NGS panel. DESIGN: We undertook a nationwide cross-sectional study of patients with pituitary adenomas with onset ≤40 years of age and/or other personal/family history of endocrine neoplasia...
May 2017: European Journal of Endocrinology
https://www.readbyqxmd.com/read/28186096/spitz-nevi-and-spitzoid-melanomas-exome-sequencing-and-comparison-with-conventional-melanocytic-nevi-and-melanomas
#7
Rossitza Lazova, Natapol Pornputtapong, Ruth Halaban, Marcus Bosenberg, Yalai Bai, Hao Chai, Michael Krauthammer
We performed exome sequencing of 77 melanocytic specimens composed of Spitz nevi (n=29), Spitzoid melanomas (n=27), and benign melanocytic nevi (n=21), and compared the results with published melanoma sequencing data. Our study highlights the prominent similarity between Spitzoid and conventional melanomas with similar copy number changes and high and equal numbers of ultraviolet-induced coding mutations affecting similar driver genes. Mutations in MEN1, PRKAR1A, and DNMT3A in Spitzoid melanomas may indicate involvement of the protein kinase A pathway, or a role of DNA methylation in the disease...
May 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28173069/a-genetic-variation-associated-with-plasma-erythropoietin-and-a-non-coding-transcript-of-prkar1a-in-sickle-cell-disease
#8
Xu Zhang, Binal N Shah, Wei Zhang, Santosh L Saraf, Galina Miasnikova, Adelina Sergueeva, Tatiana Ammosova, Xiaomei Niu, Mehdi Nouraie, Sergei Nekhai, Oswaldo Castro, Mark T Gladwin, Josef T Prchal, Joe G N Garcia, Roberto F Machado, Victor R Gordeuk
No abstract text is available yet for this article.
October 15, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28159925/mirna-1246-induces-pro-inflammatory-responses-in-mesenchymal-stem-stromal-cells-by-regulating-pka-and-pp2a
#9
Alexander Bott, Nese Erdem, Shalom Lerrer, Agnes Hotz-Wagenblatt, Christian Breunig, Khalid Abnaof, Angelika Wörner, Heike Wilhelm, Ewald Münstermann, Adit Ben-Baruch, Stefan Wiemann
The tumor microenvironment (TME) has an impact on breast cancer progression by creating a pro-inflammatory milieu within the tumor. However, little is known about the roles of miRNAs in cells of the TME during this process. We identified six putative oncomiRs in a breast cancer dataset, all strongly correlating with poor overall patient survival. Out of the six candidates, miR-1246 was upregulated in aggressive breast cancer subtypes and expressed at highest levels in mesenchymal stem/stroma cells (MSCs). Functionally, miR-1246 led to a p65-dependent increase in transcription and release of pro-inflammatory mediators IL-6, CCL2 and CCL5 in MSCs, and increased NF-κB activity...
January 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/28012237/sporadic-melanotic-schwannoma-with-overlapping-features-of-melanocytoma-bearing-a-gna11-mutation-in-an-adolescent-girl
#10
Christina Tatsi, Flora Bacopoulou, Charalampos Lyssikatos, Elena Belyavskaya, Fabio R Faucz, Constantine A Stratakis
Melanotic schwannoma (MS) is a soft tissue neoplasm that shares histologic features with melanocytic tumors and schwannomas. A type of MS, called psammomatous MS (PMS), is associated with Carney complex (CNC), which is caused by PRKAR1A mutations. Other pigmented neoplasms, such as uveal melanomas and melanocytomas (MCs), are associated with genetic defects in other genes including GNA11. We report an adolescent female with a large sporadic mesenteric MS with complex histologic findings reminiscent of both PMS and MC...
June 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28011461/antitumor-activity-of-rxdx-105-in-multiple-cancer-types-with-ret-rearrangements-or-mutations
#11
Gang G Li, Romel Somwar, James Joseph, Roger S Smith, Takuo Hayashi, Leenus Martin, Aleksandra Franovic, Anni Schairer, Eric Martin, Gregory J Riely, Jason Harris, Shunqi Yan, Ge Wei, Jennifer W Oliver, Rupal Patel, Pratik Multani, Marc Ladanyi, Alexander Drilon
Purpose: While multikinase inhibitors with RET activity are active in RET-rearranged thyroid and lung cancers, objective response rates are relatively low and toxicity can be substantial. The development of novel RET inhibitors with improved potency and/or reduced toxicity is thus an unmet need. RXDX-105 is a small molecule kinase inhibitor that potently inhibits RET. The purpose of the preclinical and clinical studies was to evaluate the potential of RXDX-105 as an effective therapy for cancers driven by RET alterations...
December 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27995993/prkar1a-is-a-functional-tumor-suppressor-inhibiting-erk-snail-e-cadherin-pathway-in-lung-adenocarcinoma
#12
Shaoqiang Wang, Yuanda Cheng, Yingying Zheng, Zhiwei He, Wei Chen, Wolong Zhou, Chaojun Duan, Chunfang Zhang
Protein Kinase cAMP-Dependent Regulatory Type I Alpha (PRKAR1A) is a tissue-specific extinguisher that transduces a signal through phosphorylation of different target proteins. Loss of PRKAR1A was frequently observed in endocrine neoplasia and stromal cell tumors. However, a few cases were seen in epithelial tumors. Previously, we first found that PRKAR1A was downregulated in lung adenocarcinoma patients. Thus, the present study aimed to clarify its clinical implication and biological function as a tumor suppressor in lung adenocarcinoma...
December 20, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27943004/carney-complex-a-familial-lentiginosis-predisposing-to-a-variety-of-tumors
#13
REVIEW
Constantine A Stratakis
Carney complex is a familial lentiginosis syndrome; these disorders cover a wide phenotypic spectrum ranging from a benign inherited predisposition to develop cutaneous spots not associated with systemic disease to associations with several syndromes. Carney complex is caused by PRKAR1A mutations and perturbations of the cyclic AMP-dependent protein kinase (PKA) signaling pathway. In addition to the cutaneous findings, the main tumors associated with Carney complex are endocrine: 1) primary pigmented nodular adrenocortical disease, a bilateral adrenal hyperplasia leading to Cushing syndrome; 2) growth-hormone secreting pituitary adenoma or pituitary somatotropic hyperplasia leading to acromegaly; 3) thyroid and gonadal tumors, including a predisposition to thyroid cancer...
September 2016: Reviews in Endocrine & Metabolic Disorders
https://www.readbyqxmd.com/read/27938411/butyrate-attenuates-lipolysis-in-adipocytes-co-cultured-with-macrophages-through-non-prostaglandin-e2-mediated-and-prostaglandin-e2-mediated-pathways
#14
Hideo Ohira, Wao Tsutsui, Rie Mamoto, Sayaka Yamaguchi, Masako Nishida, Miki Ito, Yoshio Fujioka
BACKGROUND: Interactions between adipocytes and macrophages are associated with metabolic disorders. Production of pro-inflammatory mediators and the release of free fatty acids (FFAs) increase when these cells are co-cultured; butyrate significantly diminishes these effects by suppressing both the macrophage inflammatory and adipocyte lipolysis pathways. Butyrate is known to up-regulate the expression of prostaglandin E2 (PGE2). Therefore, we hypothesized that PGE2 is associated with the suppression of lipolysis by butyrate in co-culture...
December 9, 2016: Lipids in Health and Disease
https://www.readbyqxmd.com/read/27910854/the-genetic-basis-and-fitness-consequences-of-sperm-midpiece-size-in-deer-mice
#15
Heidi S Fisher, Emily Jacobs-Palmer, Jean-Marc Lassance, Hopi E Hoekstra
An extensive array of reproductive traits varies among species, yet the genetic mechanisms that enable divergence, often over short evolutionary timescales, remain elusive. Here we examine two sister-species of Peromyscus mice with divergent mating systems. We find that the promiscuous species produces sperm with longer midpiece than the monogamous species, and midpiece size correlates positively with competitive ability and swimming performance. Using forward genetics, we identify a gene associated with midpiece length: Prkar1a, which encodes the R1α regulatory subunit of PKA...
December 2, 2016: Nature Communications
https://www.readbyqxmd.com/read/27825928/structure-of-a-pka-ri%C3%AE-recurrent-acrodysostosis-mutant-explains-defective-camp-dependent-activation
#16
Jessica Gh Bruystens, Jian Wu, Audrey Fortezzo, Jason Del Rio, Cole Nielsen, Donald K Blumenthal, Ruth Rock, Eduard Stefan, Susan S Taylor
Most disease-related mutations that impair cAMP protein kinase A (PKA) signaling are present within the regulatory (R) PKA RI alpha-subunit (RIα). Although mutations in the PRKAR1A gene are linked to Carney complex (CNC) disease and, more recently, to acrodysostosis-1 (ACRDYS1), the two diseases show contrasting phenotypes. While CNC mutations cause increased PKA activity, ACRDYS1 mutations result in decreased PKA activity and cAMP resistant holoenzymes. Mapping the ACRDYS1 disease mutations reveals their localization to the second of two tandem cAMP-binding (CNB) domains (CNB-B), and here, we characterize a recurrent deletion mutant where the last 14 residues are missing...
December 4, 2016: Journal of Molecular Biology
https://www.readbyqxmd.com/read/27813477/-genes-in-the-camp-pathway-causing-skeletal-dysplasia-with-or-without-hormonal-resistance
#17
REVIEW
Caroline Silve
Acrodysostosis refers to a heterogeneous group of rare skeletal dysplasia that share characteristic features including severe brachydactyly, facial dysostosis and nasal hypoplasia. The literature describing acrodysostosis cases has been confusing because some reported patients may have had other phenotypically related diseases presenting Albright Hereditary Osteodystrophy (AHO) such as pseudohypoparathyroidism type 1a (PHP1a) or pseudopseudohypoparathyroidism (PPHP). A question has been whether patients display or not abnormal mineral metabolism associated with resistance to PTH and/or resistance to other hormones that bind G-protein coupled receptors (GPCR) linked to Gsa, as observed in PHP1a...
2016: Biologie Aujourd'hui
https://www.readbyqxmd.com/read/27803029/prkar1a-gene-knockout-in-the-pancreas-leads-to-neuroendocrine-tumorigenesis
#18
Emmanouil Saloustros, Paraskevi Salpea, Matthew Starost, Sissi Liu, Fabio R Faucz, Edra London, Eva Szarek, Woo-Jin Song, Mehboob Hussain, Constantine A Stratakis
Carney complex (CNC) is a rare disease associated with multiple neoplasias, including a predisposition to pancreatic tumors; it is caused most frequently by the inactivation of the PRKAR1A gene, a regulator of the cyclic AMP (cAMP)-dependent kinase (PKA). The method used was to create null alleles of prkar1a in mouse cells expressing pdx1 (Δ-Prkar1a). We found that these mice developed endocrine or mixed endocrine/acinar cell carcinomas with 100% penetrance by the age of 4-5 months. Malignant behavior of the tumors was seen as evidenced by stromal invasion and metastasis to locoregional lymph nodes...
January 2017: Endocrine-related Cancer
https://www.readbyqxmd.com/read/27801954/the-world-health-organization-2016-classification-of-testicular-non-germ-cell-tumours-a-review-and-update-from-the-international-society-of-urological-pathology-testis-consultation-panel
#19
REVIEW
Muhammad T Idrees, Thomas M Ulbright, Esther Oliva, Robert H Young, Rodolfo Montironi, Lars Egevad, Daniel Berney, John R Srigley, Jonathan I Epstein, Satish K Tickoo
The World Health Organization (WHO) released a new tumour classification for the genitourinary system in early 2016 after consensus by pathologists with expertise in these organs. It utilized the framework of the 2004 classification, and incorporated the most up-to-date information concerning these tumours. In testicular tumours, the majority of the changes occurred in the nomenclature and classification of germ cell tumours; however, several modifications were also made for non-germ cell tumours. Among sex cord-stromal tumours, sclerosing Sertoli cell tumour (SCT) is no longer recognized as a separate entity but as a morphological variant of SCT not otherwise specified (NOS), as CTNNB1 gene mutations have been noted in both neoplasms but not in the other forms of SCT...
March 2017: Histopathology
https://www.readbyqxmd.com/read/27756606/screening-for-genetic-causes-of-growth-hormone-hypersecretion
#20
REVIEW
Liliya Rostomyan, Albert Beckers
Growth hormone (GH) secreting pituitary tumors may be caused by genetic abnormalities in a variety of genes including AIP, MEN1, CDKN1B, and PRKAR1A. These can lead to GH secreting pituitary adenomas as an isolated occurrence (e.g. as aggressive sporadic adenomas or in familial isolated pituitary adenomas (FIPA)) or as part of syndromic conditions such as MEN1 or Carney complex. These tumors have more aggressive features than sporadic acromegaly, including a younger age at disease onset and larger tumor size, and they can be challenging to manage...
October 2016: Growth Hormone & IGF Research
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