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Catherine Le Stunff, Francoise Tilotta, Jérémy Sadoine, Dominique Le Denmat, Claire Briet, Emmanuelle Motte, Eric Clauser, Pierre Bougnères, Catherine Chaussain, Caroline Silve
In humans, activating mutations in the PRKAR1A gene cause acrodysostosis 1 (ACRDYS1). These mutations result in a reduction in PKA activation caused by an impaired ability of cAMP to dissociate mutant PRKAR1A from catalytic PKA subunits. Two striking features of this rare developmental disease are renal resistance to PTH and chondrodysplasia resulting from the constitutive inhibition of PTHR1/Gsa/AC/cAMP/PKA signaling. We developed a knock-in of the recurrent ACRDYS1 R368X PRKAR1A mutation in the mouse. No litters were obtained from [R368X]/[+] females (thus no homozygous [R368X]/[R368X] mice)...
September 2, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Susanne Thiele, Giovanna Mantovani, Anne Barlier, Valentina Boldrin, Paolo Bordogna, Luisa de Sanctis, Francesca Elli, Kathleen Freson, Intza Garin, Virginie Grybek, Patrick Hanna, Benedetta Izzi, Olaf Hiort, Beatriz Lecumberri, Arrate Pereda, Vrinda Saraff, Caroline Silve, Serap Turan, Alessia Usardi, Ralf Werner, Guiomar Perez de Nanclares, Agnès Linglart
OBJECTIVE: Disorders caused by impairments in the parathyroid hormone (PTH) signalling pathway are historically classified under the term pseudohypoparathyroidism (PHP), that encompasses rare, related but highly heterogeneous diseases with demonstrated (epi)genetic causes. The actual classification is based on the presence or absence of specific clinical and biochemical signs together with an in vivo response to exogenous PTH and the results of an in vitro assay to measure Gsa protein activity...
July 11, 2016: European Journal of Endocrinology
Toshimi Michigami
Hypoparathyroidism in a broad sense is caused by a parathyroid hormone (PTH) deficiency or resistance, leading to hypocalcemia and hyperphosphatemia. PTH deficiency can be result from destruction or hypoplasia/agenesis of the parathyroid gland, or the impaired synthesis or secretion of PTH. On the other hand, PTH resistance is based on the disrupted transduction of its signaling and includes pseudohypoparathyroidism, Blomstrand lethal chondrodysplasia and acrodysostosis. There has been a substantial progress in the identification of the pathogenesis for the inherited hypoparathyroidism, and genetic tests for diagnosis are considered when necessary...
June 2016: Clinical Calcium
Giovanna Mantovani, Anna Spada, Francesca Marta Elli
Pseudohypoparathyroidism exemplifies an unusual form of hormone resistance as the underlying molecular defect is a partial deficiency of the α subunit of the stimulatory G protein (Gsα), a key regulator of the cAMP signalling pathway, rather than of the parathyroid hormone (PTH) receptor itself. Despite the first description of this disorder dating back to 1942, later findings have unveiled complex epigenetic alterations in addition to classic mutations in GNAS underpining the molecular basis of the main subtypes of pseudohypoparathyroidism...
June 2016: Nature Reviews. Endocrinology
Francesca Marta Elli, Paolo Bordogna, Luisa de Sanctis, Federica Giachero, Elisa Verrua, Maria Segni, Laura Mazzanti, Valentina Boldrin, Alma Toromanovic, Anna Spada, Giovanna Mantovani
The cyclic adenosine monophosphate (cAMP) intracellular signaling pathway mediates the physiological effects of several hormones and neurotransmitters, acting by the activation of G-protein coupled receptors (GPCRs) and several downstream intracellular effectors, including the heterotrimeric stimulatory G-protein (Gs), the cAMP-dependent protein kinase A (PKA), and cAMP-specific phosphodiesterases (PDEs). Defective G-protein-mediated signaling has been associated with an increasing number of disorders, including Albright hereditary osteodistrophy (AHO) and pseudohypoparathyroidism (PHP), a heterogeneous group of rare genetic metabolic disorders resulting from molecular defects at the GNAS locus...
June 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Yara Rhayem, Catherine Le Stunff, Waed Abdel Khalek, Colette Auzan, Jerome Bertherat, Agnès Linglart, Alain Couvineau, Caroline Silve, Eric Clauser
The main target of cAMP is PKA, the main regulatory subunit of which (PRKAR1A) presents mutations in two genetic disorders: acrodysostosis and Carney complex. In addition to the initial recurrent mutation (R368X) of the PRKAR1A gene, several missense and nonsense mutations have been observed recently in acrodysostosis with hormonal resistance. These mutations are located in one of the two cAMP-binding domains of the protein, and their functional characterization is presented here. Expression of each of the PRKAR1A mutants results in a reduction of forskolin-induced PKA activation (measured by a reporter assay) and an impaired ability of cAMP to dissociate PRKAR1A from the catalytic PKA subunits by BRET assay...
November 13, 2015: Journal of Biological Chemistry
Giovanna Mantovani, Francesca M Elli
The term pseudohypoparathryoidism (PHP) refers to a group of rare genetic and epigenetic disorders characterized by resistance to the action of parathyroid hormone (PTH) that activates cAMP signaling in target cells. Together with pseudohypoparathyroidism, Albright hereditary osteodystrophy (AHO) and progressive osseous heteroplasia (POH) represent rare, related and deeply impairing disorders encompassing heterogeneous features, such as brachydactyly, ectopic ossifications, short stature, mental retardation and endocrine deficiencies due to resistance to the action of different hormones...
May 2015: Annales D'endocrinologie
Caroline Silve
No abstract text is available yet for this article.
May 2015: Annales D'endocrinologie
Mark E Gurney, Emily C D'Amato, Alex B Burgin
Between 20% and 25% of patients diagnosed with Alzheimer's disease (AD) do not have amyloid burden as assessed by positron emission tomography imaging. Thus, there is a need for nonamyloid-directed therapies for AD, especially for those patients with non-amyloid AD. The family of phosphodiesterase-4 (PDE4) enzymes are underexploited therapeutic targets for central nervous system indications. While the PDE4A, B, and D subtypes are expressed in brain, the strict amino acid sequence conservation of the active site across the four subtypes of PDE4 has made it difficult to discover subtype inhibitors...
January 2015: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Nan Li, Min Nie, Mei Li, Yan Jiang, Xiaoping Xing, Ou Wang, Chunlin Li, Weibo Xia
Acrodysostosis is a rare skeletal dysplasia, which has not been reported previously in patients of Chinese origin. The PRKAR1A gene and PDE4D gene have been found to be causative genes of acrodysostosis. A Chinese girl with acrodysostosis and concomitant multiple hormone resistance was recruited for our study. Clinical and biochemical characters were analyzed. DNA was extracted from leukocytes and was sequenced for GNAS, PDE4D and PRKAR1A gene mutations. A de novo heterozygous missense mutation (c.866G>A/p...
2014: International Journal of Molecular Sciences
Tadashi Kaname, Chang-Seok Ki, Norio Niikawa, George S Baillie, Jonathan P Day, Ken-Ichi Yamamura, Tohru Ohta, Gen Nishimura, Nobuo Mastuura, Ok-Hwa Kim, Young Bae Sohn, Hyun Woo Kim, Sung Yoon Cho, Ah-Ra Ko, Jin Young Lee, Hyun Wook Kim, Sung Ho Ryu, Hwanseok Rhee, Kap-Seok Yang, Keehyoung Joo, Jooyoung Lee, Chi Hwa Kim, Kwang-Hyun Cho, Dongsan Kim, Kumiko Yanagi, Kenji Naritomi, Ko-Ichiro Yoshiura, Tatsuro Kondoh, Eiji Nii, Hidefumi Tonoki, Miles D Houslay, Dong-Kyu Jin
Acrodysostosis without hormone resistance is a rare skeletal disorder characterized by brachydactyly, nasal hypoplasia, mental retardation and occasionally developmental delay. Recently, loss-of-function mutations in the gene encoding cAMP-hydrolyzing phosphodiesterase-4D (PDE4D) have been reported to cause this rare condition but the pathomechanism has not been fully elucidated. To understand the pathogenetic mechanism of PDE4D mutations, we conducted 3D modeling studies to predict changes in the binding efficacy of cAMP to the catalytic pocket in PDE4D mutants...
November 2014: Cellular Signalling
Toshikatsu Mitsui, Ok-Hwa Kim, Christine M Hall, Amaka Offiah, Diana Johnson, Dong-Kyu Jin, Teck-Hock Toh, Shun Soneda, Dai Keino, Shohei Matsubayashi, Tomohiro Ishii, Gen Nishimura, Tomonobu Hasegawa
Acroscyphodysplasia (OMIM250215) is a distinctive form of metaphyseal dysplasia characterized by the distal femoral and proximal tibial epiphyses embedded in cup-shaped, large metaphyses known as metaphyseal scypho ("scypho" = cup) deformity. It is also associated with severe growth retardation and brachydactyly. The underlying molecular mechanism of acroscyphodysplasia has not yet been elucidated, although scypho-deformity of the knee has been reported in three patients with acrodysostosis due to a mutation in the PDE4D gene...
October 2014: American Journal of Medical Genetics. Part A
C Silve, C Le-Stunff, E Motte, Y Gunes, A Linglart, E Clauser
Acrodysostosis (ADO) 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 with 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 Gsα, as observed in PHP1a...
2012: BoneKEy Reports
Anna Lindstrand, Giedre Grigelioniene, Daniel Nilsson, Maria Pettersson, Wolfgang Hofmeister, Britt-Marie Anderlid, Sarina G Kant, Claudia A L Ruivenkamp, Peter Gustavsson, Helena Valta, Stefan Geiberger, Alexandra Topa, Kristina Lagerstedt-Robinson, Fulya Taylan, Josephine Wincent, Tobias Laurell, Minna Pekkinen, Magnus Nordenskjöld, Outi Mäkitie, Ann Nordgren
BACKGROUND: Point mutations in PDE4D have been recently linked to acrodysostosis, an autosomal dominant disorder with skeletal dysplasia, severe brachydactyly, midfacial hypoplasia and intellectual disability. The purpose of the present study was to investigate clinical and cellular implications of different types of mutations in the PDE4D gene. METHODS: We studied five acrodysostosis patients and three patients with gene dose imbalances involving PDE4D clinically and by whole exome sequencing, Sanger sequencing and array comparative hybridisation...
January 2014: Journal of Medical Genetics
Mehmet Kirnap, Mustafa Calis, Cumali Gokce, Selim Kurtoglu, Mustafa Ozturk, Fahrettin Kelestimur
An 18-year-old man was admitted to the clinic complaining of deterioration in the function of his hands and feet. The clinical examination revealed that his movements were clumsy and that he had disproportionally short limbs. In addition, he also had facial abnormalities of frontal bossing, hypertelorism, maxillary hypoplasia, broad low nasal bridge, short upturned nose with anteverted nostrils and triangular mouth. All extremities appeared short with stubby fingers and toes and with broad hands and wrinkling of the dorsal skin...
April 2013: Hormones: International Journal of Endocrinology and Metabolism
Georges Abi Lahoud, Nohra Chalouhi, Pascal Jabbour
BACKGROUND: Acrodysostosis is a rare syndrome characterized by peripheral dysostosis, nasal hypoplasia, and frequently mental retardation. Only two adult cases of acrodysostosis have been reported to have neurological symptoms. CASE DESCRIPTION: We report one additional adult case that presented with signs of spinal cord compression from spinal stenosis, and make the first histologic description in the literature of the bony anomalies seen in acrodysostosis. The patient had a T3 to T5 laminectomy and experienced a complete recovery...
September 2014: World Neurosurgery
F Muhn, E Klopocki, L Graul-Neumann, S Uhrig, A Colley, M Castori, E Lankes, W Henn, U Gruber-Sedlmayr, W Seifert, D Horn
Acrodysostosis is characterized by a peripheral dysostosis that is accompanied by short stature, midface hypoplasia, and developmental delay. Recently, it was shown that heterozygous point mutations in the PRKAR1A gene cause acrodysostosis with hormone resistance. By mutational analysis of the PRKAR1A gene we detected four different mutations (p.Arg368Stop, p.Ala213Thr, p.Tyr373Cys, and p.Arg335Cys) in four of seven affected patients with acrodysostosis. The combination of clinical results, endocrinological parameters and in silico mutation analysis gives evidence to suppose a pathogenic effect of each mutation...
December 2013: Clinical Genetics
Agnès Linglart, Helena Fryssira, Olaf Hiort, Paul-Martin Holterhus, Guiomar Perez de Nanclares, Jesús Argente, Claudine Heinrichs, Alma Kuechler, Giovanna Mantovani, Bruno Leheup, Philippe Wicart, Virginie Chassot, Dorothée Schmidt, Óscar Rubio-Cabezas, Annette Richter-Unruh, Sara Berrade, Arrate Pereda, Emese Boros, Maria Teresa Muñoz-Calvo, Marco Castori, Yasemin Gunes, Guylene Bertrand, Pierre Bougnères, Eric Clauser, Caroline Silve
CONTEXT: Acrodysostosis is a rare skeletal dysplasia that is associated with multiple resistance to G protein-coupled receptor (GPCR) signaling hormones in a subset of patients. Acrodysostosis is genetically heterogeneous because it results from heterozygous mutations in PRKAR1A or PDE4D, two key actors in the GPCR-cAMP-protein kinase A pathway. OBJECTIVE: Our objective was to identify the phenotypic features that distinguish the two genotypes causing acrodysostosis...
December 2012: Journal of Clinical Endocrinology and Metabolism
Danielle C Lynch, David A Dyment, Lijia Huang, Sarah M Nikkel, Didier Lacombe, Philippe M Campeau, Brendan Lee, Carlos A Bacino, Jacques L Michaud, Francois P Bernier, Jillian S Parboosingh, A Micheil Innes
Acrodysostosis is characterized by nasal hypoplasia, peripheral dysostosis, variable short stature, and intellectual impairment. Recently, mutations in PRKAR1A were reported in patients with acrodysostosis and hormone resistance. Subsequently, mutations in a phosphodiesterase gene (PDE4D) were identified in seven sporadic cases. We sequenced PDE4D in seven acrodysostosis patients from five families. Missense mutations were identified in all cases. Families showed de novo inheritance except one family with three affected children whose father was subsequently found to have subtle features of acrodysostosis...
January 2013: Human Mutation
C Silve, E Clauser, A Linglart
Acrodysostosis refers to a group of rare skeletal dysplasias that share in common characteristic clinical and radiological features including brachydactyly, facial dysostosis, and nasal hypoplasia. In the past, the term acrodysostosis has been used to describe patients with heterogeneous phenotypes, including, in some cases, patients that today would be given alternative diagnoses. The recent finding that mutations impairing the cAMP binding to PRKAR1A are associated with "typical" acrodysostosis and hormonal resistance initiates the era where this group of disorders can be categorized on a genetic basis...
September 2012: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
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