The broad phenotypic spectrum of PPP2R1A -related neurodevelopmental disorders correlates with the degree of biochemical dysfunction
Lenaerts, Lisa (University of Leuven)
Reynhout, Sara (KU Leuven Brain Institute (LBI))
Verbinnen, Iris (University of Leuven)
Laumonnier, Frédéric (Centre Hospitalier Régional Universitaire (Tours, França))
Toutain, Annick (Centre Hospitalier Régional Universitaire (Tours, França))
Bonnet-Brilhault, Frédérique (Centre Hospitalier Régional Universitaire)
Hoorne, Yana (University of Leuven)
Joss, Shelagh (Queen Elizabeth University Hospital, Glasgow)
Chassevent, Anna K. (Kennedy Krieger Institute)
Smith-Hicks, Constance (Kennedy Krieger Institute)
Loeys, Bart (University of Antwerp)
Joset, Pascal (University of Zurich)
Steindl, Katharina (University of Zurich)
Rauch, Anita (University of Zurich)
Mehta, Sarju G. (Addenbrookes Hospital (Cambridge, Regne Unit))
Chung, Wendy (Columbia University Medical Center)
Devriendt, Koenraad (University of Leuven)
Holder, Susan E. (North West Thames Regional Genetics Service)
Jewett, Tamison (Wake Forest University)
Baldwin, Lauren M. (Wake Forest University)
Wilson, William G. (University of Virginia)
Towner, Shelley (University of Virginia)
Srivastava, Siddharth (Boston Children's Hospital (Boston, Estats Units d'Amèrica))
Johnson, Hannah F. (Boston Children's Hospital (Boston, Estats Units d'Amèrica))
Daumer-Haas, Cornelia (Prenatal Medicine Munich)
Baethmann, Martina (Klinikum Dritter Orden München)
Ruiz, Anna (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Gabau, Elisabeth (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Jain, Vani (University Hospital of Wales)
Varghese, Vinod (University Hospital of Wales)
Al-Beshri, Ali (University of Alabama at Birmingham)
Fulton, Stephen (Le Bonheur Children's Hospital)
Wechsberg, Oded (Maccabi Healthcare Services)
Orenstein, Naama (Tel Aviv University)
Prescott, Katrina (Leeds Teaching Hospitals NHS Trust)
Childs, Anne-Marie (Leeds Teaching Hospitals NHS Trust)
Faivre, Laurence (Université de Bourgogne)
Moutton, Sébastien (Maison de Santé Bordeaux Bagatelle (Talence, França))
Sullivan, Jennifer A. (Duke University Medical Center)
Shashi, Vandana (Duke University Medical Center)
Koudijs, Suzanne M. (Maastricht UMC+)
Heijligers, Malou (Maastricht UMC+)
Kivuva, Emma (Royal Devon & Exeter NHS Foundation Trust)
McTague, Amy (Great Ormond Street Hospital for Children (Londres))
Male, Alison M. (Great Ormond Street Hospital for Children (Londres))
van Ierland, Yvette (Erasmus Medical Center)
Plecko, Barbara (Medical University of Graz)
Maystadt, Isabelle (Institut de Pathologie et de Génétique)
Hamid, Rizwan (Vanderbilt University Medical Center)
Hannig, Vickie L. (Vanderbilt University Medical Center)
Houge, Gunnar (Haukeland University Hospital (Bergen, Noruega))
Janssens, Veerle (KU Leuven Brain Institute (LBI))
Universitat Autònoma de Barcelona

Data:	2020
Resum:	Neurodevelopmental disorders (NDD) caused by protein phosphatase 2A (PP2A) dysfunction have mainly been associated with de novo variants in PPP2R5D and PPP2CA, and more rarely in PPP2R1A. Here, we aimed to better understand the latter by characterizing 30 individuals with de novo and often recurrent variants in this PP2A scaffolding Aα subunit. Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. We describe 30 individuals with 16 different variants in PPP2R1A, 21 of whom had variants not previously reported. The severity of developmental delay ranged from mild learning problems to severe intellectual disability (ID) with or without epilepsy. Common features were language delay, hypotonia, and hypermobile joints. Macrocephaly was only seen in individuals without B55α subunit-binding deficit, and these patients had less severe ID and no seizures. Biochemically more disruptive variants with impaired B55α but increased striatin binding were associated with profound ID, epilepsy, corpus callosum hypoplasia, and sometimes microcephaly. We significantly expand the phenotypic spectrum of PPP2R1A -related NDD, revealing a broader clinical presentation of the patients and that the functional consequences of the variants are more diverse than previously reported.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra, i la creació d'obres derivades, sempre que no sigui amb finalitats comercials i que es distribueixin sota la mateixa llicència que regula l'obra original. Cal que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	PPP2R1A ; PP2A ; Intellectual disability ; Neurodevelopmental disorder ; Epilepsy
Publicat a:	Genetics in medicine, Vol. 23 Num. 2 (feb. 2021) , p. 352-362, ISSN 1530-0366

DOI: 10.1038/s41436-020-00981-2
PMID: 33106617

11 p, 1014.2 KB

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