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Stratakis Lab: Section on Endocrinology and Genetics

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Research Areas

We aim to understand the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those disorders that are developmental, hereditary, and associated with adrenal hypoplasia or hyperplasia, multiple tumors, and abnormalities in other endocrine glands. We study congenital adrenal hypoplasia caused by triple A syndrome and several endocrine deficiencies; familial hyperaldosteronism; adrenocortical and thyroid cancer; pituitary tumors; multiple endocrine neoplasia (MEN) syndromes affecting the pituitary, thyroid, and adrenal glands; and the Carney complex (CNC), an autosomal dominant disease. We focus on cyclic AMP (cAMP)/protein kinase A (PKA)–stimulated signaling pathways and PKA effects on tumor suppression, development, and the cell cycle. The PRKAR1A and pde11a gene mouse models, in which we have knocked out the respective genes, facilitate our research. Genome-wide searches for other genes responsible for CNC and related diseases of the adrenal and pituitary glands are ongoing. We described a new disease (the Carney-Stratakis syndrome, or CSS) and observed adrenocortical tumors in association with tumors of the peripheral nervous system and gastrointestinal system (the Carney Triad, or CT). The laboratory identified mutations in the succinate dehydrogenase subunits B, C, and D in CSS and, in collaboration with other investigators and the NCI, is currently looking for gene(s) responsible for CT and related tumors.

Carney complex genetics

We have collected families with CNC and related syndromes from several collaborating institutions worldwide. Through genetic linkage analysis, we identified loci harboring genes for CNC on chromosomes 2 (2p16) and 17 (17q22–24) and are currently searching for other possible loci for this genetically heterogeneous condition. With the application of state-of-the-art molecular cytogenetic techniques, we are investigating the participation of these currently identified genomic loci in the expression of the disease and have constructed a comprehensive genetic and physical map of the 2p16 chromosomal region for cloning the CNC-associated sequences from this region. Studies in cultured primary tumor cell lines (established from our patients) identified a region of genomic amplification in CNC tumors in the center of the map. The PRKAR1A gene on 17q22–24, the gene responsible for CNC in most cases of the disease, appears to undergo loss of heterozygosity in at least some CNC tumors. PRKAR1A is also the main regulatory subunit (subunit type 1-α) of PKA, a central signaling pathway for many cellular functions and hormonal responses. We have increased the number of CNC patients in genotype-phenotype correlation studies, which are expected to provide insight into the complex biochemical and molecular pathways regulated by PRKAR1A and PKA. We expect to identify new genes by ongoing genome-wide searches for patients and families who do not carry PRKAR1A mutations.

PRKAR1A, protein kinase A activity, and endocrine and other tumor development

We are investigating the functional and genetic consequences of PRKAR1A mutations in cell lines established from CNC patients and their tumors. We measure both cAMP and PKA activity in these cell lines, along with the expression of the other subunits of the PKA tetramer. In addition, we are seeking mutations of the PRKAR1A gene in sporadic endocrine and non-endocrine tumors (thyroid adenomas and carcinomas, adrenocortical adenomas and carcinomas, ovarian carcinomas, melanomas and other benign and malignant pigmented lesions, and myxomas in the heart and other sites)—mutations that would further establish the gene's role as a general tumor suppressor. Many investigators within the NIH and around the world provide specimens on a collaborative basis.

PRKAR1A+/− and antisense (AS) PRKAR1A transgenic animal models

In collaboration with Heiner Westphal, Lawrence Kirschner, while in our laboratory, developed a PRKAR1A knockout mouse floxed by a lox-P system for the purpose of generating, first, a novel PRKAR1A+/- and, second, knockouts of the PRKAR1A gene in a tissue-specific manner after crossing the new mouse model with mice expressing the cre protein in the adrenal cortex, anterior lobe of the pituitary, and thyroid gland (Kirschner et al., Cancer Res 2005;65:4506). The heterozygote mouse develops several tumors reminiscent of the equivalent human disease. Ongoing crosses with mice such as the transgenic GHRH–expressing mouse attempt to identify tissue-specific effects (the pituitary in the case of the GHRH–expressing mouse) or specific signaling events (such as involvement of the p53 and Rb proteins in Prkara1a-related tumorigenesis). We also created a transgenic mouse carrying an antisense transgene for exon 2 of the mouse PRKAR1A gene (X2AS) under the control of a regulatable promoter. As in human CNC tumors, tissues from mice with the X2AS transgene showed elevated cAMP-stimulated kinase activity. The mice had several CNC-compatible histologic and clinical changes, including obesity attributed to subclinical Cushing syndrome.

PRKAR1A, the cell cycle, and other signaling pathways

We work to identify PRKAR1A-interacting mitogenic and other growth-signaling pathways in cell lines expressing PRKAR1A constructs and/or mutations. Several genes that regulate PKA function and increase cAMP-dependent proliferation and related signals may be altered in the process of endocrine tumorigenesis initiated by a mutant PRKAR1A, a gene with important functions in the cell cycle and in chromosomal stability. Recently, we found an interaction with the mTOR pathway in both human and mouse cells with altered PKA function.

Phosphodiesterase (PDE) genes in endocrine and other tumors

In patients who did not exhibit CNC or PRKAR1A mutations but presented with bilateral adrenal tumors similar to those in CNC, we found inactivating mutations of the PDE11A gene, which encodes phosphodiesterase-11A that regulates PKA in the normal physiologic state. Phosphodiesterase 11A is a member of a 22 gene–encoded family of proteins that break down cyclic nucleotides controlling PKA. PDE11A appears to act as a tumor suppressor such that tumors develop when its action is abolished. In what proved to be the first cases in which mutated PDE was observed in a genetic disorder predisposing to tumors, we found pediatric and adult patients with bilateral adrenal tumors. Recent data indicate that PDE11A sequence polymorphisms may be present in the general population. The finding that genetic alterations of such a major biochemical pathway may be associated with tumors in humans raises the reasonable hope that drugs that modify PKA and/or PDE activity may eventually BE developed for use in both CNC and patients with other, non-genetic, adrenal tumors—and perhaps other endocrine tumors. Most recently, we identified a patient with a PDE8B mutation and Cushing syndrome, with the PDE8B transcript and protein seemingly expressed widely in the endocrine system.

Genetic investigations into other adrenocortical diseases and related tumors

Through collaborations, we (1) apply general and pathway-specific microarrays to a variety of adrenocortical tumors, including single adenomas and massive macronodular adrenocortical disease (MMAD), to identify genes with important functions in adrenal oncogenetics; (2) examine candidate genes for their roles in adrenocortical tumors and development; and (3) identify additional genes that play a role in inherited adrenocortical and related diseases, such as Allgrove syndrome.

Genetic investigations into pituitary tumors, other endocrine neoplasias, and related syndromes

In collaboration with several other investigators at the NIH and elsewhere, we are investigating the genetics of CNC- and adrenal-related endocrine tumors, including childhood pituitary tumors, related or unrelated to PRKAR1A mutations. As part of this work, we have identified novel genetic abnormalities in other endocrine glands.

Genetic investigations into other endocrine neoplasias and related syndromes; hereditary paragangliomas and related conditions

As part of a collaboration with other investigators at the NIH and elsewhere (including an international consortium organized by our laboratory), we are studying the genetics of a rare syndrome that predisposes to adrenal and other tumors, the Carney Triad, and related conditions (associated with gastrointestinal stromal tumors, or GIST). In the course of our work, we identified a patient with a new syndrome, known as the paraganglioma and gastrointestinal stromal tumor syndrome (or Carney-Stratakis syndrome), for which we found mutations in the genes encoding succinate dehydrogenase (SDH) subunits B, C, and D. In another patient, we found a novel germline mutation of the PDFGRA gene.

Clinical investigations into the diagnosis and treatment of adrenal and pituitary tumors

Patients with adrenal tumors and other types of Cushing syndrome (and occasionally other pituitary tumors) come to the NIH Clinical Center for diagnosis and treatment. Ongoing investigations focus on (1) the prevalence of ectopic hormone receptor expression in adrenal adenomas and massive macronodular adrenocortical disease; (2) the diagnostic use of high-sensitivity magnetic resonance imaging for the earlier detection of pituitary tumors; and (3) the diagnosis, management, and post-operative care of children with Cushing syndrome and other pituitary tumors.

Clinical and molecular investigations into other pediatric genetic syndromes

Largely in collaboration with a number of other investigators at the NIH and elsewhere, we are conducting work on pediatric genetic syndromes seen in our clinics and wards.

Last Updated Date: 11/30/2012
Last Reviewed Date: 11/30/2012

Contact Information

Name: Dr Constantine A Stratakis
Senior Investigator
Section on Endocrinology and Genetics
Phone: 301-594-5984
Fax: 301-480-6480

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