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With the surgical improvement of congenital heart disease, Fontan operation has been applied to many complicated patients in recent years. This is the first report of a child with panhypopituitarism who underwent Fontan operation. A 5-year-old boy was scheduled for Fontan operation. He previously underwent Blalock-Taussig shunt and bidirectional Glenn operations for univentricular heart with double-outlet right ventricle and pulmonary atresia. He was receiving hydrocortisone and 1-desamino-8-D-arginine vasopressin (DDAVP) for panhypopituitarism secondary to removal of craniopharyngioma performed at the age of three years. Although urine output and serum sodium concentration were adequately controlled by adjustment of vasopressin infusion rate during surgery, massive pleural effusions and ascites developed postoperatively, which required several days for control by adjusting the dose of oral DDAVP and normalize the serum sodium level. Intraoperative management of Fontan operation for a patient with panhypopituitarism was controllable by appropriate hormone replacement. However, postoperative fluid management was complicated by the clinical features of panhypopituitarism and Fontan physiology., Author(s): Kohei Sunoki [sup.1], Yoji Otsuka [sup.1], Hidetaka Iwai [sup.1], Tatsuya Nagano [sup.1], Naoyuki Taga [sup.1], Masaaki Kawada [sup.2], Mamoru Takeuchi [sup.1] [sup.3] Author Affiliations: (1) grid.410804.9, 0000000123090000, Department of [...]

Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disease characterized by extraskeletal bone formation through endochondral ossification. Patients with FOP harbor point mutations in ACVR1, a type I receptor for BMPs. Although mutated ACVR1 (FOP-ACVR1) has been shown to render hyperactivity in BMP signaling, we and others have uncovered a mechanism by which FOP-ACVR1 mistransduces BMP signaling in response to Activin -A, a molecule that normally transduces TGF-[beta] signaling. Although Activin-A evokes enhanced chondrogenesis in vitro and heterotopic ossification (HO) in vivo, the underlying mechanisms have yet to be revealed. To this end, we developed a high -throughput screening (HTS) system using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to identify pivotal pathways in enhanced chondrogenesis that are initiated by Activin-A. In a screen of 6,809 small-molecule compounds, we identified mTOR signaling as a critical pathway for the aberrant chondrogenesis of mesenchymal stromal cells derived from FOP-iPSCs (FOP-iMSCs). Two different HO mouse models, an FOP model mouse expressing FOP-ACVR1 and an FOP-iPSC-based HO model mouse, revealed critical roles for mTOR signaling in vivo. Moreover, we identified ENPP2, an enzyme that generates lysophosphatidic acid, as a linker of FOP-ACVR1 and mTOR signaling in chondrogenesis. These results uncovered the crucial role of the Activin-A/FOP-ACVR1/ ENPP2/mTOR axis in FOP pathogenesis., Introduction Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease characterized by extraskeletal bone formation in soft tissue, where bone normally does not exist. Ectopic bones are formed through endochondral [...]

Branching morphogenesis of the ureteric bud (UB) is a key developmental process that controls organogenesis of the entire metanephros. Notably, aberrant UB branching may result in a spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). Genetic, biochemical and physiological studies have demonstrated that the renin-angiotensin system (RAS), a key regulator of the blood pressure and fluid/electrolyte homeostasis, also plays a critical role in kidney development. All the components of the RAS are expressed in the metanephros. Moreover, mutations in the genes encoding components of the RAS in mice or humans cause diverse types of CAKUT which include renal papillary hypoplasia, hydronephrosis, duplicated collecting system, renal tubular dysgenesis, renal vascular abnormalities, abnormal glomerulogenesis and urinary concentrating defect. Despite widely accepted role of the RAS in metanephric kidney and renal collecting system (ureter, pelvis, calyces and collecting ducts) development, the mechanisms by which an intact RAS exerts its morphogenetic actions are incompletely defined. Emerging evidence indicates that defects in UB branching morphogenesis may be causally linked to the pathogenesis of renal collecting system anomalies observed under conditions of aberrant RAS signaling. This review describes the role of the RAS in UB branching morphogenesis and highlights emerging insights into the cellular and molecular mechanisms whereby RAS regulates this critical morphogenetic process. Keywords Kidney development * Ureteric bud * Renin-angiotensin * GDNF * Ret * EGF receptor, Introduction Branching morphogenesis of the ureteric bud (UB) is a fundamental developmental process that controls organogenesis of the metanephros. Notably, derangements in UB morphogenesis cause a spectrum of congenital anomalies [...]

Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes. It has thus been suggested that primary and/or genetic abnormalities in mitochondrial function may lead to accumulation of toxic [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2010.06.001 Byline: Vincent Cantagrel (1), Dirk J. Lefeber (2)(3), Bobby G. Ng (7), Ziqiang Guan (8), Jennifer L. Silhavy (1), Stephanie L. Bielas (1), Ludwig Lehle (9), Hans Hombauer (10), Maciej Adamowicz (11), Ewa Swiezewska (13), Arjan P. De Brouwer (4), Peter Blumel (14), Jolanta Sykut-Cegielska (12), Scott Houliston (7), Dominika Swistun (1), Bassam R. Ali (15), William B. Dobyns (17), Dusica Babovic-Vuksanovic (18), Hans van Bokhoven (4)(5), Ron A. Wevers (2), Christian R.H. Raetz (8), Hudson H. Freeze (7), Eva Morava (6), Lihadh Al-Gazali (15)(16), Joseph G. Gleeson (1) Keywords: HUMDISEASE; CHEMBIO Abstract: N-linked glycosylation is the most frequent modification of secreted and membrane-bound proteins in eukaryotic cells, disruption of which is the basis of the congenital disorders of glycosylation (CDGs). We describe a new type of CDG caused by mutations in the steroid 5[alpha]-reductase type 3 (SRD5A3) gene. Patients have mental retardation and ophthalmologic and cerebellar defects. We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation. Author Affiliation: (1) Neurogenetics Laboratory, Institute for Genomic Medicine, Howard Hughes Medical Institute, Department of Neurosciences and Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA (2) Department of Laboratory Medicine, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands (3) Department of Neurology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands (4) Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands (5) Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands (6) Department of Paediatrics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands (7) Genetic Disease Program, Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA (8) Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA (9) Universitat Regensburg, Lehrstuhl fur Zellbiologie und Pflanzenbiochemie, D-93053 Regensburg, Germany (10) Ludwig Institute for Cancer Research, Department of Medicine, Department of Cellular and Molecular Medicine and Cancer Center, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA (11) Department of Biochemistry and Experimental Medicine, The Children's Memorial Health Institute, 04-730 Warsaw, Poland (12) Department of Metabolic Diseases, Endocrinology, and Diabetology, The Children's Memorial Health Institute, 04-730 Warsaw, Poland (13) Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland (14) Preyer'sches Kinderspital, 1100 Vienna, Austria (15) Department of Pathology, United Arab Emirates University, School of Medicine and Health Sciences, 17666 Al Ain, United Arab Emirates (16) Department of Pediatrics, United Arab Emirates University, School of Medicine and Health Sciences, 17666 Al Ain, United Arab Emirates (17) Department of Human Genetics, Neurology, and Pediatrics, University of Chicago, Chicago, IL 60637, USA (18) Departments of Medical Genetics, Pediatric Neurology, Laboratory Genetics, Pediatric Endocrinology, and Dermatology, Mayo Clinic, Rochester, MN 55905, USA Article History: Received 30 January 2010; Revised 26 March 2010; Accepted 6 May 2010 Article Note: (miscellaneous) Published online: July 15, 2010

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.12.008 Byline: James W. Dennis (1)(2), Ivan R. Nabi (3), Michael Demetriou (4) Abstract: Genetic information flows from DNA to macromolecular structures -- the dominant force in the molecular organization of life. However, recent work suggests that metabolite availability to the hexosamine and Golgi N-glycosylation pathways exerts control over the assembly of macromolecular complexes on the cell surface and, in this capacity, acts upstream of signaling and gene expression. The structure and number of N-glycans per protein molecule cooperate to regulate lectin binding and thereby the distribution of glycoproteins at the cell surface. Congenital disorders of glycosylation provide insight as extreme hypomorphisms, whereas milder deficiencies may encompass many common chronic conditions, including autoimmunity, metabolic syndrome, and aging. Author Affiliation: (1) Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue R988, Toronto, Ontario M5G 1X5, Canada (2) Departments of Molecular Genetics, Laboratory Medicine, and Pathology, University of Toronto, Toronto, Ontario M5S 1A8, Canada (3) Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada (4) Department of Neurology and Department of Microbiology and Molecular Genetics, Institute for Immunology, University of California, Irvine, Irvine, CA 92697, USA

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2009.04.021 Byline: Hideo Ohuchi (a), Yoshihiro Miyamoto (b), Masaki Yamamoto (a), Haruko Ishihara (a), Hidemi Takata (a), Aya Miyazaki (a), Osamu Yamada (a), Toshikatsu Yagihara (c) Abstract: Abnormal glucose metabolism (AGM) adversely impacts morbidity and mortality in patients with chronic heart failure. No data on AGM in adult patients with congenital heart disease (ACHD) are available. Author Affiliation: (a) Department of Pediatrics, National Cardiovascular Center, Osaka, Japan (b) Department of Atherosclerosis and Diabetes, National Cardiovascular Center, Osaka, Japan (c) Department of Thoracic Surgery, National Cardiovascular Center, Osaka, Japan Article History: Received 18 December 2008; Accepted 2 April 2009