Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome.

Autor:	Palencia-Campos A; Instituto de Investigaciones Biomédicas 'Alberto Sols,' Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, 28029, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, 28029, Spain., Aoto PC; Department of Pharmacology, University of California, San Diego, 9400 Gilman Drive, La Jolla, CA 92093-0654, USA., Machal EMF; Institute for Biology, Department of Biochemistry, University of Kassel, Kassel, 34132, Germany., Rivera-Barahona A; Instituto de Investigaciones Biomédicas 'Alberto Sols,' Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, 28029, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, 28029, Spain., Soto-Bielicka P; Instituto de Investigaciones Biomédicas 'Alberto Sols,' Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, 28029, Spain., Bertinetti D; Institute for Biology, Department of Biochemistry, University of Kassel, Kassel, 34132, Germany., Baker B; Department of Pharmacology, University of California, San Diego, 9400 Gilman Drive, La Jolla, CA 92093-0654, USA., Vu L; Department of Pharmacology, University of California, San Diego, 9400 Gilman Drive, La Jolla, CA 92093-0654, USA., Piceci-Sparascio F; Medical Genetics Unit, Casa Sollievo della Sofferenza Foundation, IRCCS, San Giovanni Rotondo, 71013, Italy., Torrente I; Medical Genetics Unit, Casa Sollievo della Sofferenza Foundation, IRCCS, San Giovanni Rotondo, 71013, Italy., Boudin E; Department of Medical Genetics, University of Antwerp, Edegem, 2650, Belgium., Peeters S; Department of Medical Genetics, University of Antwerp, Edegem, 2650, Belgium., Van Hul W; Department of Medical Genetics, University of Antwerp, Edegem, 2650, Belgium., Huber C; Clinical Genetics and Reference Center for Skeletal Dysplasia, AP-HP, Necker-Enfants Malades Hospital, Paris, 75015, France; Université De Paris, INSERM UMR1163, Institut Imagine, Paris, 75015, France., Bonneau D; Biochemistry and Genetics Department, Angers Hospital, Angers Cedex 9, 49933, France; UMR CNRS 6015-INSERM U1083, MitoVasc Institute, Angers University, Angers Cedex 9, 49933, France., Hildebrand MS; Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia; Murdoch Children's Research Institute, Parkville, 3052, Victoria, Australia., Coleman M; Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia; Murdoch Children's Research Institute, Parkville, 3052, Victoria, Australia., Bahlo M; Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, 3010, Victoria, Australia., Bennett MF; Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia; Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia; Department of Medical Biology, University of Melbourne, Melbourne, 3010, Victoria, Australia., Schneider AL; Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia., Scheffer IE; Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia; Murdoch Children's Research Institute, Parkville, 3052, Victoria, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, and Florey Institute of Neuroscience and Mental Health, Parkville, 3052, Victoria, Australia., Kibæk M; Children's Hospital of H.C. Andersen, Odense University Hospital, 5000 Odense, Denmark., Kristiansen BS; Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark., Issa MY; Department of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt., Mehrez MI; Department of Oro-dental Genetics, Division of Human Genetics and Genome Research. Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt., Ismail S; Department of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt., Tenorio J; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, 28029, Spain; Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Universidad Autónoma, Madrid, 28046, Spain; ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability., Li G; Division for Molecular Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, 0316, Norway., Skålhegg BS; Division for Molecular Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, 0316, Norway., Otaify GA; Department of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt., Temtamy S; Department of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt., Aglan M; Department of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt., Jønch AE; Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark., De Luca A; Medical Genetics Unit, Casa Sollievo della Sofferenza Foundation, IRCCS, San Giovanni Rotondo, 71013, Italy., Mortier G; Department of Medical Genetics, University of Antwerp, Edegem, 2650, Belgium; Antwerp University Hospital, Edegem, 2650, Belgium., Cormier-Daire V; Clinical Genetics and Reference Center for Skeletal Dysplasia, AP-HP, Necker-Enfants Malades Hospital, Paris, 75015, France; Université De Paris, INSERM UMR1163, Institut Imagine, Paris, 75015, France., Ziegler A; Biochemistry and Genetics Department, Angers Hospital, Angers Cedex 9, 49933, France; UMR CNRS 6015-INSERM U1083, MitoVasc Institute, Angers University, Angers Cedex 9, 49933, France., Wallis M; School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, 7001, Australia; Clinical Genetics Service, Austin Health, Heidelberg, 3084, Victoria, Australia., Lapunzina P; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, 28029, Spain; Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Universidad Autónoma, Madrid, 28046, Spain; ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability., Herberg FW; Institute for Biology, Department of Biochemistry, University of Kassel, Kassel, 34132, Germany., Taylor SS; Department of Pharmacology, University of California, San Diego, 9400 Gilman Drive, La Jolla, CA 92093-0654, USA; Department of Chemistry and Biochemistry, University of California, San Diego, 9400 Gilman Drive, La Jolla, CA 92093-0654, USA., Ruiz-Perez VL; Instituto de Investigaciones Biomédicas 'Alberto Sols,' Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, 28029, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, 28029, Spain; Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Universidad Autónoma, Madrid, 28046, Spain; ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability. Electronic address: vlruiz@iib.uam.es.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2020 Nov 05; Vol. 107 (5), pp. 977-988. Date of Electronic Publication: 2020 Oct 14.
DOI:	10.1016/j.ajhg.2020.09.005
Abstrakt:	PRKACA and PRKACB code for two catalytic subunits (Cα and Cβ) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual. We investigated the structural and functional consequences of the variants identified in PRKACA and PRKACB through the use of several computational and experimental approaches, and we found that they lead to PKA holoenzymes which are more sensitive to activation by cAMP than are the wild-type proteins. Furthermore, expression of PRKACA or PRKACB variants detected in the affected individuals inhibited hedgehog signaling in NIH 3T3 fibroblasts, thereby providing an underlying mechanism for the developmental defects observed in these cases. Our findings highlight the importance of both Cα and Cβ subunits of PKA during human development. (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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