2. Academic Validation
  3. Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome

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

  • Am J Hum Genet. 2020 Nov 5;107(5):977-988. doi: 10.1016/j.ajhg.2020.09.005.
Adrian Palencia-Campos 1,  Phillip C Aoto 2,  Erik M F Machal 3,  Ana Rivera-Barahona 1,  Patricia Soto-Bielicka 4,  Daniela Bertinetti 3,  Blaine Baker 2,  Lily Vu 2,  Francesca Piceci-Sparascio 5,  Isabella Torrente 5,  Eveline Boudin 6,  Silke Peeters 6,  Wim Van Hul 6,  Celine Huber 7,  Dominique Bonneau 8,  Michael S Hildebrand 9,  Matthew Coleman 9,  Melanie Bahlo 10,  Mark F Bennett 11,  Amy L Schneider 12,  Ingrid E Scheffer 13,  Maria Kibæk 14,  Britta S Kristiansen 15,  Mahmoud Y Issa 16,  Mennat I Mehrez 17,  Samira Ismail 16,  Jair Tenorio 18,  Gaoyang Li 19,  Bjørn Steen Skålhegg 19,  Ghada A Otaify 16,  Samia Temtamy 16,  Mona Aglan 16,  Aia E Jønch 15,  Alessandro De Luca 5,  Geert Mortier 20,  Valérie Cormier-Daire 7,  Alban Ziegler 8,  Mathew Wallis 21,  Pablo Lapunzina 18,  Friedrich W Herberg 3,  Susan S Taylor 22,  Victor L Ruiz-Perez 23
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Pharmacology, University of California, San Diego, 9400 Gilman Drive, La Jolla, CA 92093-0654, USA.
  • 3 Institute for Biology, Department of Biochemistry, University of Kassel, Kassel, 34132, Germany.
  • 4 Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, 28029, Spain.
  • 5 Medical Genetics Unit, Casa Sollievo della Sofferenza Foundation, IRCCS, San Giovanni Rotondo, 71013, Italy.
  • 6 Department of Medical Genetics, University of Antwerp, Edegem, 2650, Belgium.
  • 7 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.
  • 8 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.
  • 9 Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia; Murdoch Children's Research Institute, Parkville, 3052, Victoria, Australia.
  • 10 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.
  • 11 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.
  • 12 Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia.
  • 13 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.
  • 14 Children's Hospital of H.C. Andersen, Odense University Hospital, 5000 Odense, Denmark.
  • 15 Department of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark.
  • 16 Department of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt.
  • 17 Department of Oro-dental Genetics, Division of Human Genetics and Genome Research. Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt.
  • 18 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.
  • 19 Division for Molecular Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, 0316, Norway.
  • 20 Department of Medical Genetics, University of Antwerp, Edegem, 2650, Belgium; Antwerp University Hospital, Edegem, 2650, Belgium.
  • 21 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.
  • 22 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.
  • 23 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.
PMID: 33058759 DOI: 10.1016/j.ajhg.2020.09.005
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.

Keywords

Ellis-van Creveld syndrome; GLI transcritpion factors; PKA; PRKACA; PRKACB; cAMP signaling; congenital heart defects; hedgehog signaling; mosaicism; postaxial polydactyly.

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