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Bo Zhang, Uyen Tran, Oliver Wessely
The development of the kidney relies on the establishment and maintenance of a precise tubular diameter of its functional units, the nephrons. This process is disrupted in Polycystic Kidney Disease (PKD) resulting in dilations of the nephron and renal cyst formation. In the course of exploring G-protein coupled signaling in the Xenopus pronephric kidney we discovered that loss of the G-protein alpha subunit Gnas results in a PKD phenotype. Polycystin-1, one of the genes mutated in human PKD, encodes for a protein resembling a G-protein coupled receptor...
March 12, 2018: Development
Arrate Pereda, Intza Garin, Guiomar Perez de Nanclares
BACKGROUND: Pseudohypoparathyroidism (PHP) is a rare disease whose phenotypic features are rather difficult to identify in some cases. Thus, although these patients may present with the Albright's hereditary osteodystrophy (AHO) phenotype, which is characterized by small stature, obesity with a rounded face, subcutaneous ossifications, mental retardation and brachydactyly, its manifestations are somewhat variable. Indeed, some of them present with a complete phenotype, whereas others show only subtle manifestations...
March 2, 2018: BMC Medical Genetics
Chung Thong Lim, Márta Korbonits
Pituitary adenomas are the third most common central nervous system tumours and arise from the anterior pituitary within the pituitary fossa. The signs and symptoms of patients with pituitary adenomas vary from 'mass effects' caused by a large adenoma to features secondary to excess pituitary hormones produced by the functioning pituitary adenoma. Detailed histopathological assessment, based on novel classifications and the latest WHO guidelines, helps to categorise pituitary adenomas into different subtypes and identify features that, in some cases, help to predict their behaviour...
March 2, 2018: Endocrine Practice
Andy Madrid, Pankaj Chopra, Reid S Alisch
Human evolution from non-human primates has seen substantial change in the central nervous system, with the molecular mechanisms underlying human brain evolution remaining largely unknown. Methylation of cytosine at the fifth carbon (5-methylcytosine; 5 mC) is an essential epigenetic mark linked to neurodevelopment, as well as neurological disease. The emergence of another modified form of cytosine (5-hydroxymethylcytosine; 5 hmC) that is enriched in the brain further substantiates a role for these epigenetic marks in neurodevelopment, yet little is known about the evolutionary importance of these marks in brain development...
2018: Frontiers in Molecular Neuroscience
H Ostertag, S Glombitza
Fibrous dysplasia of bone is a connatal but not hereditary disease with monostotic or polyostotic manifestations and may be associated either with the extraskeletal disease McCune-Albright syndrome or with myxoma of the skeletal muscle, termed Mazabraud syndrome.The confirmation of recurrent chromosomal aberrations may lead to the conclusion that fibrous dysplasia is a neoplasia rather than a dysplastic skeletal disease.The primary cause of all forms of the described diseases is the activating GNAS mutation, which is detectable in almost all lesions...
February 27, 2018: Der Pathologe
Mirella Hage, Say Viengchareun, Erika Brunet, Chiara Villa, Dominique Pineau, Jérôme Bouligand, Jean Paul Teglas, Clovis Adam, Fabrice Parker, Marc Lombès, Gérard Tachdjian, Stéphane Gaillard, Philippe Chanson, Lucie Tosca, Peter Kamenický
Purpose: The molecular pathogenesis of growth hormone (GH)-secreting pituitary adenomas is not fully understood. Cytogenetic alterations might serve as alternative driver events in GNAS mutation-negative somatotroph tumors. Experimental Design: We performed cytogenetic profiling of pituitary adenomas obtained from 39 acromegalic patients and 4 patients with sporadic gigantism by using array comparative genomic hybridization (array-CGH) analysis. We explored intratumor DNA copy-number heterogeneity in two tumor samples by using DNA fluorescence in situ hybridization (FISH)...
February 21, 2018: Journal of Clinical Endocrinology and Metabolism
Anara Karaca, Vijayram Reddy Malladi, Yan Zhu, Olta Tafaj, Elena Paltrinieri, Joy Y Wu, Qing He, Murat Bastepe
GNAS mutations leading to constitutively active stimulatory G protein alpha-subunit (Gsα) cause different tumors, fibrous dysplasia of bone, and McCune-Albright syndrome, which are typically not associated with short stature. Enhanced signaling of the parathyroid hormone/parathyroid hormone-related peptide receptor, which couples to multiple G proteins including Gsα, leads to short bones with delayed endochondral ossification. It has remained unknown whether constitutive Gsα activity also impairs bone growth...
February 20, 2018: Bone
Arrate Pereda, Jose Maria Martos-Tello, Intza Garin, Javier Errea-Dorronsoro, Guiomar Perez de Nanclares
Progressive osseous heteroplasia (POH, OMIM#166350) is an "ultrarare" genetic condition characterized by plaque-like heterotopic ossification, beginning in infancy in the dermis and subsequently progressing to involve deep connective tissues such as muscles and joints, sometimes resulting in loss of mobility1 . It is usually associated with paternal inheritance of an inactivating mutation at the GNAS gene but in some patients (around 30% of cases) with identical clinical characteristics of POH no mutations have been detected2 ...
February 21, 2018: Clinical Endocrinology
Steven B Maron, Lindsay Alpert, Heewon A Kwak, Samantha Lomnicki, Leah Chase, David Xu, Emily O'Day, Rebecca J Nagy, Richard B Lanman, Fabiola Cecchi, Todd Hembrough, Alexa Schrock, John Hart, Shu-Yuan Xiao, Namrata Setia, Daniel V T Catenacci
Previous anti-EGFR trials in unselected gastroesophageal adenocarcinoma (GEA) patients were resoundingly negative. We identified EGFR amplification in 5% (19/363) of patients at the University of Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy. Seven pts received >1 dose of treatment: three first line FOLFOX plus ABT-806, one second line FOLFIRI plus cetuximab, and three third/fourth line cetuximab alone. Treatment achieved objective response in 58% (4/7) and disease control in 100% (7/7) with a median progression-free survival of 10 months...
February 15, 2018: Cancer Discovery
Francesca Marta Elli, Paolo Bordogna, Maura Arosio, Anna Spada, Giovanna Mantovani
Background: Pseudohypoparathyroidism type 1B (PHP1B; MIM#603233) is a rare imprinting disorder (ID), associated with the GNAS locus, characterized by parathyroid hormone (PTH) resistance in the absence of other endocrine or physical abnormalities. Sporadic PHP1B cases, with no known underlying primary genetic lesions, could represent true stochastic errors in early embryonic maintenance of methylation. Previous data confirmed the existence of different degrees of methylation defects associated with PHP1B and suggested the presence of mosaicism, a phenomenon already described in the context of other IDs...
2018: Clinical Epigenetics
Nicholas J Goel, Laura L Meyers, Myrto Frangos
Pseudohypoparathyroidism type 1B (PHP1B) is characterized by renal tubular resistance to parathyroid hormone (PTH) leading to hyperphosphatemia, hypocalcemia, elevated PTH, and hyperparathyroid bone changes. PHP1B is an imprinting disorder that results from loss of methylation at the maternal GNAS gene, which suppresses transcription of the alpha subunit of the stimulatory G protein of the PTH receptor. Emerging evidence supports an association between assisted reproductive technologies (ART) and imprinting disorders; however, there is currently little evidence linking PHP1B and ART...
February 7, 2018: Journal of Assisted Reproduction and Genetics
Wenya Linda Bi, Alexandra Giantini Larsen, Ian F Dunn
PURPOSE OF REVIEW: Pituitary tumors are undergoing a transformation in histopathologic and molecular classification, coincident with the continued refinement of increasingly powerful methods of genomic annotation and discovery. We highlight novel genomic alterations identified in pituitary adenomas and craniopharyngiomas and discuss their clinical implications. RECENT FINDINGS: Sporadic pituitary adenomas are associated with relatively few recurrent somatic mutations...
February 2, 2018: Current Neurology and Neuroscience Reports
Shinichiro Sano, Akie Nakamura, Keiko Matsubara, Keisuke Nagasaki, Maki Fukami, Masayo Kagami, Tsutomu Ogata
Context: Pseudohypoparathyroidism type I (PHP-I) is divided into PHP-Ia with Albright hereditary osteodystrophy and PHP-Ib, which usually shows no Albright hereditary osteodystrophy features. Although PHP-Ia and PHP-Ib are typically caused by genetic defects involving α subunit of the stimulatory G protein (Gsα)-coding GNAS exons and methylation defects of the GNAS differentially methylated regions (DMRs) on the maternal allele, respectively, detailed phenotypic characteristics still remains to be examined...
January 1, 2018: Journal of the Endocrine Society
R Laguna-Barraza, M J Sánchez-Calabuig, A Gutiérrez-Adán, D Rizos, S Pérez-Cerezales
This study examines the effects of the histone deacetylation inhibitor scriptaid (SCR) on preimplantation embryo development in vitro and on imprinting gene expression. We hypothesized that SCR would increase histone acetylation levels, enhance embryonic genome activation, and regulate imprinting and X-chromosome inactivation (XCI) in in vitro produced bovine embryos. Zygotes were cultured in vitro in presence or absence of SCR added at different time points. We assessed cleavage and blastocyst rates as well as the quality of blastocysts through: (i) differential cell counts; (ii) survival after vitrification/thawing and (iii) gene expression analysis -including imprinted genes...
January 11, 2018: Theriogenology
Li Wang, Shaoyan Chang, Zhen Wang, Shan Wang, Junsheng Huo, Gangqiang Ding, Rui Li, Chi Liu, Shaofang Shangguan, Xiaolin Lu, Ting Zhang, Zhiyong Qiu, Jianxin Wu
Disturbed epigenetic modifications have been linked to the pathogenesis of Neural Tube Defects (NTDs) in those with folate deficiency during pregnancy. However, evidence is lacking to delineate the critical region in epigenome regulated by parental folic acid and mechanisms by which folate deficiency affects normal embryogenesis. Our data from clinical samples revealed the presence of aberrant DNA methylation in GNAS imprinting cluster in NTD samples with low folate concentrations. Results from mouse models indicated that the establishment of GNAS imprinting was influenced by both maternal and paternal folate-deficient diets...
December 19, 2017: Oncotarget
Erina Suzuki, Ryosuke Bo, Kaori Sue, Hiroyuki Awano, Tsutomu Ogata, Satoshi Narumi, Masayo Kagami, Shinichiro Sano, Maki Fukami
Germline intragenic mutations in the GNAS locus result in pseudohypoparathyroidism type 1a (PHP1a) and related conditions. Nearly half of the previously reported GNAS intragenic mutations were structural variants, including 3 tandem duplications of 12-25 bp. However, the precise mutation spectrum and the genomic basis of GNAS structural variants remain to be clarified. Here, we report a de novo 50-bp tandem duplication in GNAS (c.723_772dup50, p.Glu259Leufs*29) identified in a patient with typical clinical features of PHP1a...
January 11, 2018: Cytogenetic and Genome Research
Matthew Amalfitano, Billie Fyfe, Sumi V Thomas, Kevin P Egan, Meiqi Xu, Andrew G Smith, Frederick S Kaplan, Eileen M Shore, Robert J Pignolo
Mesenteric heterotopic ossification (MHO) is very rare and occurs in mid- to late-adulthood, usually in the context of prior abdominal surgery. The mechanisms of MHO are unknown. Here we describe the case of a 72-year-old man with MHO. Standard histological staining revealed that MHO occurred through an endochondral process. By comparison to known mutations in genetic conditions of HO such as fibrodysplasia ossificans progressiva (FOP) and progressive osseous heteroplasia (POH), DNA sequencing analysis demonstrated the presence of a commonly occurring heterozygous synonymous polymorphism (c...
January 7, 2018: Bone
Ana Arpón, Fermín I Milagro, Cristina Razquin, Dolores Corella, Ramón Estruch, Montserrat Fitó, Amelia Marti, Miguel A Martínez-González, Emilio Ros, Jordi Salas-Salvadó, José-Ignacio Riezu-Boj, J Alfredo Martínez
DNA methylation could be reversible and mouldable by environmental factors, such as dietary exposures. The objective was to analyse whether an intervention with two Mediterranean diets, one rich in extra-virgin olive oil (MedDiet + EVOO) and the other one in nuts (MedDiet + nuts), was influencing the methylation status of peripheral white blood cells (PWBCs) genes. A subset of 36 representative individuals were selected within the PREvención con DIeta MEDiterránea (PREDIMED-Navarra) trial, with three intervention groups in high cardiovascular risk volunteers: MedDiet + EVOO, MedDiet + nuts, and a low-fat control group...
December 23, 2017: Nutrients
Xuefeng Zhao, Peng Deng, Ramiro Iglesias-Bartolome, Panomwat Amornphimoltham, Dana J Steffen, Yunyun Jin, Alfredo A Molinolo, Luis Fernandez de Castro, Diana Ovejero, Quan Yuan, Qianming Chen, Xianglong Han, Ding Bai, Susan S Taylor, Yingzi Yang, Michael T Collins, J Silvio Gutkind
Fibrous dysplasia (FD) is a disease caused by postzygotic activating mutations of GNAS (R201C and R201H) that encode the α-subunit of the Gs stimulatory protein. FD is characterized by the development of areas of abnormal fibroosseous tissue in the bones, resulting in skeletal deformities, fractures, and pain. Despite the well-defined genetic alterations underlying FD, whether GNAS activation is sufficient for FD initiation and the molecular and cellular consequences of GNAS mutations remains largely unresolved, and there are no currently available targeted therapeutic options for FD...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
Serap Turan
Disorders related to parathyroid hormone (PTH) resistance and PTH signaling pathway impairment are historically classified under the term of pseudohypoparathyroidism (PHP). The disease was first described and named by Fuller Albright and colleagues in 1942. Albright hereditary osteodystrophy (AHO) is described as an associated clinical entity with PHP, characterized by brachydactyly, subcutaneous ossifications, round face, short stature and a stocky build. The classification of PHP is further divided into PHP-Ia, pseudo-PHP (pPHP), PHP-Ib, PHP-Ic and PHP-II according to the presence or absence of AHO, together with an in vivo response to exogenous PTH and the measurement of Gsα protein activity in peripheral erythrocyte membranes in vitro...
December 30, 2017: Journal of Clinical Research in Pediatric Endocrinology
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