Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/25159
Title: Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome.
Austin Authors: Palencia-Campos, Adrian;Aoto, Phillip C;Machal, Erik M F;Rivera-Barahona, Ana;Soto-Bielicka, Patricia;Bertinetti, Daniela;Baker, Blaine;Vu, Lily;Piceci-Sparascio, Francesca;Torrente, Isabella;Boudin, Eveline;Peeters, Silke;Van Hul, Wim;Huber, Celine;Bonneau, Dominique;Hildebrand, Michael S ;Coleman, Matthew;Bahlo, Melanie;Bennett, Mark F ;Schneider, Amy L ;Scheffer, Ingrid E ;Kibæk, Maria;Kristiansen, Britta S;Issa, Mahmoud Y;Mehrez, Mennat I;Ismail, Samira;Tenorio, Jair;Li, Gaoyang;Skålhegg, Bjørn Steen;Otaify, Ghada A;Temtamy, Samia;Aglan, Mona;Jønch, Aia E;De Luca, Alessandro;Mortier, Geert;Cormier-Daire, Valérie;Ziegler, Alban;Wallis, Mathew J ;Lapunzina, Pablo;Herberg, Friedrich W;Taylor, Susan S;Ruiz-Perez, Victor L
Affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, 9400 Gilman Drive, La Jolla, CA 92093-0654, USA
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
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
UMR CNRS 6015-INSERM U1083, MitoVasc Institute, Angers University, Angers Cedex 9, 49933, France
Epilepsy Research Centre
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
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
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..
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
Biochemistry and Genetics Department, Angers Hospital, Angers Cedex 9, 49933, France
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
Department of Pharmacology, University of California, San Diego, 9400 Gilman Drive, La Jolla, CA 92093-0654, USA
Murdoch Children's Research Institute, Parkville, 3052, Victoria, Australia
Department of Medical Biology, University of Melbourne, Melbourne, 3010, Victoria, Australia
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia
School of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, 7001, Australia
Institute for Biology, Department of Biochemistry, University of Kassel, Kassel, 34132, Germany
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 Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, 28029, Spain
Institute for Biology, Department of Biochemistry, University of Kassel, Kassel, 34132, Germany
Department of Pharmacology, University of California, San Diego, 9400 Gilman Drive, La Jolla, CA 92093-0654, USA
Medical Genetics Unit, Casa Sollievo della Sofferenza Foundation, IRCCS, San Giovanni Rotondo, 71013, Italy
Department of Medical Genetics, University of Antwerp, Edegem, 2650, Belgium..
Children's Hospital of H.C. Andersen, Odense University Hospital, 5000 Odense, Denmark
Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark
Department of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt
Department of Oro-dental Genetics, Division of Human Genetics and Genome Research. Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt
Department of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt
Division for Molecular Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, 0316, Norway
Department of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt
Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark
Medical Genetics Unit, Casa Sollievo della Sofferenza Foundation, IRCCS, San Giovanni Rotondo, 71013, Italy
Department of Medical Genetics, University of Antwerp, Edegem, 2650, Belgium; Antwerp University Hospital, Edegem, 2650, Belgium
Institute for Biology, Department of Biochemistry, University of Kassel, Kassel, 34132, Germany
|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
Clinical Genetics
Issue Date: 14-Oct-2020
metadata.dc.date: 2020-10-14
Publication information: American Journal of Human Genetics 2020; online first: 14 October
Abstract: 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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/25159
DOI: 10.1016/j.ajhg.2020.09.005
PubMed URL: 33058759
Type: Journal Article
Subjects: Ellis-van Creveld syndrome
GLI transcritpion factors
PKA
PRKACA
PRKACB
cAMP signaling
congenital heart defects
hedgehog signaling
mosaicism
postaxial polydactyly
Appears in Collections:Journal articles

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