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

Adrian Palencia-Campos; Phillip C Aoto; Erik M F Machal; Ana Rivera-Barahona; Patricia Soto-Bielicka; Daniela Bertinetti; Blaine Baker; Lily Vu; Francesca Piceci-Sparascio; Isabella Torrente; Eveline Boudin; Silke Peeters; Wim Van Hul; Celine Huber; Dominique Bonneau; Michael S Hildebrand; Matthew Coleman; Melanie Bahlo; Mark F Bennett; Amy L Schneider; Ingrid E Scheffer; Maria Kibæk; Britta S Kristiansen; Mahmoud Y Issa; Mennat I Mehrez; Samira Ismail; Jair Tenorio; Gaoyang Li; Bjørn Steen Skålhegg; Ghada A Otaify; Samia Temtamy; Mona Aglan; Aia E Jønch; Alessandro De Luca; Geert Mortier; Valérie Cormier-Daire; Alban Ziegler; Mathew Wallis; Pablo Lapunzina; Friedrich W Herberg; Susan S Taylor; Victor L Ruiz-Perez

doi:10.1016/j.ajhg.2020.09.005

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. Epub 2020 Oct 14.

Authors

Adrian Palencia-Campos¹, Phillip C Aoto², Erik M F Machal³, Ana Rivera-Barahona¹, Patricia Soto-Bielicka⁴, Daniela Bertinetti³, Blaine Baker², Lily Vu², Francesca Piceci-Sparascio⁵, Isabella Torrente⁵, Eveline Boudin⁶, Silke Peeters⁶, Wim Van Hul⁶, Celine Huber⁷, Dominique Bonneau⁸, Michael S Hildebrand⁹, Matthew Coleman⁹, Melanie Bahlo¹⁰, Mark F Bennett¹¹, Amy L Schneider¹², Ingrid E Scheffer¹³, Maria Kibæk¹⁴, Britta S Kristiansen¹⁵, Mahmoud Y Issa¹⁶, Mennat I Mehrez¹⁷, Samira Ismail¹⁶, Jair Tenorio¹⁸, Gaoyang Li¹⁹, Bjørn Steen Skålhegg¹⁹, Ghada A Otaify¹⁶, Samia Temtamy¹⁶, Mona Aglan¹⁶, Aia E Jønch¹⁵, Alessandro De Luca⁵, Geert Mortier²⁰, Valérie Cormier-Daire⁷, Alban Ziegler⁸, Mathew Wallis²¹, Pablo Lapunzina¹⁸, Friedrich W Herberg³, Susan S Taylor²², Victor L Ruiz-Perez²³

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple / diagnosis
Abnormalities, Multiple / genetics*
Abnormalities, Multiple / pathology
Adolescent
Adult
Animals
Base Sequence
Cognitive Dysfunction / diagnosis
Cognitive Dysfunction / genetics*
Cognitive Dysfunction / pathology
Cyclic AMP / metabolism
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / chemistry
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / deficiency
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / genetics*
Female
Fingers / abnormalities*
Fingers / pathology
Gene Expression Regulation, Developmental
Germ-Line Mutation*
Heart Septal Defects / diagnosis
Heart Septal Defects / genetics*
Heart Septal Defects / pathology
Hedgehog Proteins / genetics
Hedgehog Proteins / metabolism
Holoenzymes / chemistry
Holoenzymes / deficiency
Holoenzymes / genetics
Humans
Infant, Newborn
Male
Mice
Models, Molecular
Mosaicism
NIH 3T3 Cells
Pedigree
Polydactyly / diagnosis
Polydactyly / genetics*
Polydactyly / pathology
Protein Structure, Secondary
Toes / abnormalities*
Toes / pathology

Substances

Hedgehog Proteins
Holoenzymes
Cyclic AMP
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
PRKACA protein, human
PRKACB protein, human

Supplementary concepts

Atrioventricular Septal Defect
Polydactyly, Postaxial

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding