A5030754052- Cardiac tumors and thrombi
- Peptidase Inhibition and Analysis
- Phosphodiesterase function and regulation
- RNA Research and Splicing
- Cancer-related molecular mechanisms research
- Cancer Genomics and Diagnostics
- Cancer-related gene regulation
- Sarcoma Diagnosis and Treatment
- Adrenal and Paraganglionic Tumors
- Single-cell and spatial transcriptomics
- Prostate Cancer Treatment and Research
- RNA regulation and disease
- RNA modifications and cancer
- Histone Deacetylase Inhibitors Research
- Pituitary Gland Disorders and Treatments
- Renin-Angiotensin System Studies
- Molecular Biology Techniques and Applications
- Cancer, Hypoxia, and Metabolism
- Hormonal Regulation and Hypertension
- Congenital heart defects research
- Testicular diseases and treatments
- Genomics and Phylogenetic Studies
- Protein Degradation and Inhibitors
- Virus-based gene therapy research
- Vascular Tumors and Angiosarcomas
George Washington University
2016-2025
McCormick (United States)
2013-2024
Institute of Electrical and Electronics Engineers
2024
Health and Human Development (2HD) Research Network
2023
Broad Institute
2018-2019
Genomics (United Kingdom)
2019
National Institutes of Health
2006-2015
Eunice Kennedy Shriver National Institute of Child Health and Human Development
2006-2015
Pediatrics and Genetics
2008-2015
Georgetown University
2014
The "complex of myxomas, spotty skin pigmentation, and endocrine overactivity," or "Carney complex" (CNC), is caused by inactivating mutations the regulatory subunit type 1A cAMP-dependent protein kinase (PRKAR1A) gene as yet unknown defect(s) in other gene(s). Delineation a genotype-phenotype correlation for CNC patients essential understanding PRKAR1A function providing counseling preventive care.A transatlantic consortium studied molecular genotype clinical phenotype 353 (221 females 132...
Increased secretion of growth hormone leads to gigantism in children and acromegaly adults; the genetic causes are poorly understood.We performed clinical studies samples obtained from 43 patients with then sequenced an implicated gene 248 acromegaly.We observed microduplication on chromosome Xq26.3 13 gigantism; these samples, 4 were members two unrelated kindreds, 9 sporadic cases. All had disease onset during early childhood. Of who did not carry microduplication, none presented before...
Stratakis CA, Tichomirowa MA, Boikos S, Azevedo MF, Lodish M, Martari Verma Daly AF, Raygada Keil Papademetriou J, Drori‐Herishanu L, Horvath A, Tsang KM, Nesterova Franklin Vanbellinghen J‐F, Bours V, Salvatori R, Beckers A. The role of germline AIP , MEN1, PRKAR1A CDKN1B and CDKN2C mutations in causing pituitary adenomas a large cohort children, adolescents, patients with genetic syndromes. prevalence MEN1 CDKN2CI is unknown among pediatric (PA). In this study, we screened children PA for...
Breast cancer transcriptome acquires a myriad of regulation changes, and splicing is critical for the cell to "tailor-make" specific functional transcripts. We systematically revealed signatures three most common types breast tumors using RNA sequencing: TNBC, non-TNBC HER2-positive cancer. discovered subtype differentially spliced genes splice isoforms not previously recognized in human transcriptome. Further, we showed that exon skip intron retention are predominant events In addition,...
PRKAR1A encodes the regulatory subunit type 1-alpha (RIα) of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA). Inactivating mutations are known to be responsible for multiple neoplasia and lentiginosis syndrome Carney complex (CNC). To date, at least 117 pathogenic variants in have been identified (online database: http://prkar1a.nichd.nih.gov). The majority subject nonsense mediated mRNA decay (NMD), leading RIα haploinsufficiency and, as a result, activated cAMP...
Abstract Age-related macular degeneration is a major cause of vision impairment in the Western world among people 55 years and older. Recently we have shown that autophagy dysfunctional retinal pigment epithelium (RPE) AMD donor eyes (AMD RPE). We also showed increased reactive oxygen (ROS) production, cytoplasmic glycogen accumulation, mitochondrial dysfunction disintegration, enlarged annular LAMP-1-positive organelles RPE. However, underlying mechanisms inducing these abnormalities remain...
HIV infection has a profound effect on "bystander" cells causing metabolic co-morbidities. This may be mediated by exosomes secreted HIV-infected and containing viral factors. Here we show that HIV-1 protein Nef (exNef) are rapidly taken up macrophages releasing into the cell interior. caused down-regulation of ABCA1, reduction cholesterol efflux sharp elevation abundance lipid rafts through reduced activation small GTPase Cdc42 decreased actin polymerization. Changes in led to...
Abstract Clinical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific events critical drivers aggressiveness and therapeutic resistance African American (AA) men. AA-enriched splice variants PIK3CD , FGFR3 TSC2 RASGRP2 contribute greater oncogenic compared...
Platelet-like particles (PLPs), derived from megakaryocytic cell lines MEG-01 and K-562, are widely used as a surrogate to study platelet formation function. We demonstrate by RNA-Seq that PLPs transcriptionally distinct platelets. Expression of key genes in signaling pathways promoting activation/aggregation, such the PI3K/AKT, protein kinase A, phospholipase C, α-adrenergic GP6 receptor pathways, was missing or under-expressed PLPs. Functionally, do not aggregate following epinephrine,...
Primary pigmented nodular adrenocortical disease (PPNAD), a rare cause of corticotropin-independent Cushing syndrome, can be part Carney complex (CNC), an autosomal dominant multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac myxomas, and endocrine tumors or isolated (i). Germline PRKAR1A-inactivating mutations have been observed in both CNC iPPNAD, but with no apparent genotype-phenotype correlation.The objectives the study were detailed phenotyping for...
Abstract Purpose: We have reported previously nonsense inactivating mutations of the phosphodiesterase 11A (PDE11A) gene in patients with micronodular adrenocortical hyperplasia and Cushing syndrome. The aim this study is to investigate presence somatic or germ-line PDE11A various types tumors: ACTH-independent macronodular (AIMAH), adenoma (ACA), cancer (ACC). Experimental Design: was sequenced 117 tumors 192 controls subjects; immunohistochemistry for tumor cyclic AMP levels were studied a...
Carney complex (CNC) is an autosomal dominant multiple neoplasia, caused mostly by inactivating mutations of the regulatory subunit 1A protein kinase A (PRKAR1A). Primary pigmented nodular adrenocortical disease (PPNAD) most frequent endocrine manifestation CNC with a great inter-individual variability. Germline, protein-truncating phosphodiesterase type 11A (PDE11A) have been described to predispose variety tumors, including adrenal and testicular tumors.Our objective was investigate role...
Primary pigmented nodular adrenocortical disease (PPNAD) leads to Cushing syndrome (CS) and is often associated with Carney complex (CNC). Genetic alterations of the type 1-alpha regulatory subunit cAMP-dependent protein kinase A (PRKAR1A) phosphodiesterase 11A4 (PDE11A) genes have been found in PPNAD. Recent studies demonstrated that beta-catenin mutations are frequent adenomas carcinomas Wnt-signalling pathway involved PPNAD tumorigenesis. We hypothesized form context may harbour mutations.
Abstract Purpose: Since the identification of PRKAR1A mutations in Carney complex, substitutions and small insertions/deletions have been found ∼70% patients. To date, no germ-line deletion and/or insertion exceeded a few base pairs (up to 15). Although families map chromosome 2, it is possible that current sequencing techniques do not detect larger gene changes PRKAR1A–mutation-negative individuals with complex. Experimental Design: screen for gross alterations gene, we applied Southern...
Genetic aberrations in various components of cAMP signalling pathway predispose to endocrine tumours. Mutations the phosphodiesterases (PDEs) are involved predisposition adrenocortical neoplastic conditions.
Abstract Several types of adrenocortical tumors that lead to Cushing syndrome may be caused by aberrant cyclic AMP (cAMP) signaling. We recently identified patients with micronodular hyperplasia who were carriers inactivating mutations in the 2q-located phosphodiesterase 11A (PDE11A) gene. now studied frequency two missense substitutions, R804H and R867G, conserved regions enzyme several sets normal controls, including 745 individuals enrolled a longitudinal cohort study, New York Cancer...
Abstract Inactivating germline mutations in phosphodiesterase 11A (PDE11A) have been implicated adrenal tumor susceptibility. PDE11A is highly expressed endocrine steroidogenic tissues, especially the testis, and mice with inactivated Pde11a exhibit male infertility, a known testicular germ cell (TGCT) risk factor. We sequenced gene-coding region 95 patients TGCT from 64 unrelated kindreds. identified 8 nonsynonymous substitutions 20 15 families: four (R52T, F258Y, G291R, V820M) were newly...
Phosphodiesterases (PDEs) are key regulatory enzymes of intracellular cAMP levels. PDE11A function has been linked to predisposition adrenocortical tumors.The aim the study was gene in a large cohort patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH) and control subjects.The entire coding region sequenced 46 AIMAH 192 controls. Two variants found were transiently expressed HEK 293 H295R cells for further functional studies.The frequency all significantly higher among...