ArticleAmerican journal of human genetics2020
Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome.
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Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 50 citations in OpenAlex.
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- Classification of Cushing's syndrome PKAc mutants based upon their ability to bind PKI.The Biochemical journal · 2023Article
- Article
- Clinical variability in DYNC2H1-related skeletal ciliopathies includes Ellis-van Creveld syndrome.European journal of human genetics : EJHG · 2023Article
- mvPPT: A Highly Efficient and Sensitive Pathogenicity Prediction Tool for Missense Variants.Genomics, proteomics & bioinformatics · 2023Article
- EVC-EVC2 complex stability and ciliary targeting are regulated by modification with ubiquitin and SUMO.Frontiers in cell and developmental biology · 2023Article
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Authors and funding
42 authors at 20 institutions in 11 countries.
Adrian Palencia-CamposInstituto 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.
Phillip C AotoDepartment of Pharmacology, University of California, San Diego, 9400 Gilman Drive, La Jolla, CA 92093-0654, USA.
Erik M F MachalInstitute for Biology, Department of Biochemistry, University of Kassel, Kassel, 34132, Germany.
Ana Rivera-BarahonaInstituto 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.
Patricia Soto-BielickaInstituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, 28029, Spain.
Daniela BertinettiInstitute for Biology, Department of Biochemistry, University of Kassel, Kassel, 34132, Germany.
Blaine BakerDepartment of Pharmacology, University of California, San Diego, 9400 Gilman Drive, La Jolla, CA 92093-0654, USA.
Lily VuDepartment of Pharmacology, University of California, San Diego, 9400 Gilman Drive, La Jolla, CA 92093-0654, USA.
Francesca Piceci-SparascioMedical Genetics Unit, Casa Sollievo della Sofferenza Foundation, IRCCS, San Giovanni Rotondo, 71013, Italy.
Isabella TorrenteMedical Genetics Unit, Casa Sollievo della Sofferenza Foundation, IRCCS, San Giovanni Rotondo, 71013, Italy.
Eveline BoudinDepartment of Medical Genetics, University of Antwerp, Edegem, 2650, Belgium.
Silke PeetersDepartment of Medical Genetics, University of Antwerp, Edegem, 2650, Belgium.
Wim Van HulDepartment of Medical Genetics, University of Antwerp, Edegem, 2650, Belgium.
Celine HuberClinical 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.
Dominique BonneauBiochemistry and Genetics Department, Angers Hospital, Angers Cedex 9, 49933, France; UMR CNRS 6015-INSERM U1083, MitoVasc Institute, Angers University, Angers Cedex 9, 49933, France.
Michael S HildebrandEpilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia; Murdoch Children's Research Institute, Parkville, 3052, Victoria, Australia.
Matthew ColemanEpilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia; Murdoch Children's Research Institute, Parkville, 3052, Victoria, Australia.
Melanie BahloPopulation 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.
Mark F BennettEpilepsy 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.
Amy L SchneiderEpilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia.
Ingrid E SchefferEpilepsy 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.
Maria KibækChildren's Hospital of H.C. Andersen, Odense University Hospital, 5000 Odense, Denmark.
Britta S KristiansenDepartment of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark.
Mahmoud Y IssaDepartment of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt.
Mennat I MehrezDepartment of Oro-dental Genetics, Division of Human Genetics and Genome Research. Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt.
Samira IsmailDepartment of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt.
Jair TenorioCIBER 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.
Gaoyang LiDivision for Molecular Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, 0316, Norway.
Bjørn Steen SkålheggDivision for Molecular Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, 0316, Norway.
Ghada A OtaifyDepartment of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt.
Samia TemtamyDepartment of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt.
Mona AglanDepartment of Clinical Genetics, Division of Human Genetics and Genome Research, Center of Excellence for Human Genetics, National Research Centre, Cairo, 12622, Egypt.
Aia E JønchDepartment of Clinical Genetics, Odense University Hospital, 5000 Odense, Denmark.
Alessandro De LucaMedical Genetics Unit, Casa Sollievo della Sofferenza Foundation, IRCCS, San Giovanni Rotondo, 71013, Italy.
Geert MortierDepartment of Medical Genetics, University of Antwerp, Edegem, 2650, Belgium; Antwerp University Hospital, Edegem, 2650, Belgium.
Valérie Cormier-DaireClinical 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.
Alban ZieglerBiochemistry and Genetics Department, Angers Hospital, Angers Cedex 9, 49933, France; UMR CNRS 6015-INSERM U1083, MitoVasc Institute, Angers University, Angers Cedex 9, 49933, France.
Mathew WallisSchool of Medicine and Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, 7001, Australia; Clinical Genetics Service, Austin Health, Heidelberg, 3084, Victoria, Australia.
Pablo LapunzinaCIBER 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.
Friedrich W HerbergInstitute for Biology, Department of Biochemistry, University of Kassel, Kassel, 34132, Germany.
Susan S TaylorDepartment 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.
Victor L Ruiz-PerezInstituto 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.
National Research Centre · EGUniversity of California, San Diego · USOdense University Hospital · DKUniversity of Antwerp · BEUniversity of Kassel · DEUniversity of Melbourne · AUAustin Health · AUERN GUARD-Heart · NLIstituti di Ricovero e Cura a Carattere Scientifico · ITUniversidad Autónoma de Madrid · ESUniversité d'Angers · FRUniversity of Oslo · NOAntwerp University Hospital · BECasa Sollievo della Sofferenza · ITFlorey Institute of Neuroscience and Mental Health · AUHôpital Necker-Enfants Malades · FRInserm · FRInstituto de Investigaciones Biomédicas Sols-Morreale · ESInstituto de Salud Carlos III · ESWalter and Eliza Hall Institute of Medical Research · AU
Funding
Lessons Learned from PKA: Assembly of Dynamic Macromolecular SwitchesR35GM130389 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SUSAN S. TAYLOR · 2019 to 2026
$5.7MIlluminating the Role of understudied PRKACB Splice Variants in PKA SignalingR03TR002947 · NCATS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI TAYLOR, SUSAN S. · 2019 to 2019
$158kNCATS NIH HHS R03 TR002947NIGMS NIH HHS R35 GM130389
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.
Indexed as
Germ-Line MutationAbnormalities, MultipleAdolescentAdultAnimalsBase SequenceCognitive DysfunctionCyclic AMPCyclic AMP-Dependent Protein Kinase Catalytic SubunitsFemaleFingersGene Expression Regulation, DevelopmentalHeart Septal DefectsHedgehog ProteinsHoloenzymesHumansCyclic AMPCyclic AMP-Dependent Protein Kinase Catalytic SubunitsHedgehog ProteinsHoloenzymesPRKACA protein, humanPRKACB protein, humancAMP signalingcongenital heart defectsEllis-van Creveld syndromeGLI transcritpion factorshedgehog signalingmosaicismPKApostaxial polydactylyPRKACAPRKACB
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