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The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction

Lisa Lenaerts 1 Sara Reynhout 1 Iris Verbinnen 1 Frederic Laumonnier 2, 3 Annick Toutain 2, 3 Frédérique Bonnet-Brilhault 2, 4 yana Hoorne 1 Shelagh Joss 5 Anna Chassevent 6 Constance Smith-Hicks 6 Bart Loeys 7 Pascal Joset 8 Katharina Steindl 8 Anita Rauch 8 Sarju Mehta 9 Wendy Chung 10 Koenraad Devriendt 1 Susan Holder 11 Tamison Jewett 12 Lauren Baldwin 12 William Wilson 13 Shelley Towner 13 Siddharth Srivastava 14 Hannah Johnson 14 Cornelia Daumer-Haas 15 Martina Baethmann 16 Anna Ruiz 17 Elisabeth Gabau 17 Vani Jain 18 Vinod Varghese 18 Ali Al-Beshri 19 Stephen Fulton 20 Oded Wechsberg 21 Naama Orenstein 21, 22 Katrina Prescott 23 Anne-Marie Childs 23 Laurence Faivre 24 Sébastien Moutton 25 Jennifer Sullivan 26 Vandana Shashi 26 Suzanne Koudijs 27 Malou Heijligers 27 Emma Kivuva 28 Amy Mctague 29 Alison Male 29 yvette van Ierland 30 Barbara Plecko 31 Isabelle Maystadt 32 Rizwan Hamid 33 Vickie Hannig 33 Gunnar Houge 34 Veerle Janssens 1, 35 
24 Equipe GAD (LNC - U1231)
LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
Abstract : Purpose: 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. Methods: Most cases were identified through routine clinical diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits. Results: 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. Conclusion: 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.
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Contributor : Frédéric Laumonnier Connect in order to contact the contributor
Submitted on : Tuesday, June 29, 2021 - 11:05:38 AM
Last modification on : Friday, May 20, 2022 - 9:06:40 AM
Long-term archiving on: : Thursday, September 30, 2021 - 6:26:50 PM


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Lisa Lenaerts, Sara Reynhout, Iris Verbinnen, Frederic Laumonnier, Annick Toutain, et al.. The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction. Genetics in Medicine, Nature Publishing Group, 2021, 23 (2), pp.352-362. ⟨10.1038/s41436-020-00981-2⟩. ⟨inserm-03273405⟩



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