De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders

Reynhout, Sara; Jansen, Sandra; Haesen, Dorien; Belle, Siska Van; Munnik, Sonja A de; Bongers, Ernie M.H.F.; Schieving, Jolanda; Marcelis, Carlo; Amiel, Jeanne; Rio, Marlène; McLaughlin, Heather; Ladda, Roger L.; Sell, Susan L.; Kriek, Marjolein; Peeters-Scholte, Cacha; Terhal, Paulien A; Gassen, Koen van; Verbeek, Nienke E.; Henry, Sonja; Schwoerer, Jessica Scott; Malik, Saleem; Revençu, Nicole; Ferreira, Carlos R.; Macnamara, Ellen; Braakman, Hilde M. H.; Brimble, Elise; Ruzhnikov, Maura; Wagner, Matias; Harrer, Philip; Wieczorek, Dagmar; Kuechler, Alma; Tziperman, Barak; Barel, Ortal; Vries, Bert B.A. de; Gordon, Christopher T; Janssens, Veerle; Vissers, Lisenka E.L.M.

doi:10.1016/j.ajhg.2019.01.003

Cited by 20 publications

(46 citation statements)

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“…De novo mutations of ppp2ca highlight its importance in neurodevelopmental disorders. 64 These findings suggest that miR-203 is an important regulator of epileptogenesis; however, its effects on epileptogenesis require more experimental evidence. Except for the roles of miR-203 in epilepsy, the effects of miR-203 in other CNS diseases remain unknown and require further evidence.…”

Section: Mir-203mentioning

confidence: 99%

“…Bioinformatic analysis of miRNAs and mRNAs microarray profiling showed that miR‐203 targeting protein phosphatase 2A catalytic subunit α (ppp2ca) aggravated seizure activity at 24 hours and 28 days in the pilocarpine‐induced mouse model, 63 but further functional studies are needed to confirm their relationship. De novo mutations of ppp2ca highlight its importance in neurodevelopmental disorders 64 . These findings suggest that miR‐203 is an important regulator of epileptogenesis; however, its effects on epileptogenesis require more experimental evidence.…”

Section: Mir‐203mentioning

confidence: 99%

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MicroRNAs and target genes in epileptogenesis

et al. 2020

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Epilepsy is a chronic brain dysfunction. Current antiepileptic medicines cannot prevent epileptogenesis. Increasing data have shown that microRNAs (miRNAs) are selectively altered within the epileptic hippocampi of experimental models and human tissues, and these alterations affect the genes that control epileptogenesis. Furthermore, manipulation of miRNAs in animal models can modify epileptogenesis. As a result, miRNAs have been proposed as promising targets for treating epilepsy. We searched PubMed using the terms "microRNAs/miRNAs AND epilepsy", "microRNAs/miRNAs AND epileptogenesis", and "microRNAs/miRNAs AND seizure". We selected the articles in which the relationship between miRNAs and target gene(s) was validated and manipulation of miRNAs in in vivo epilepsy models modified epileptogenesis during the chronic phase via gene regulation. A total of 13 miRNAs were found in the present review. Based on the current analysis of miRNAs and their target gene(s), each miRNA has limitations as a potential epilepsy target. Importantly, miR-211 or miR-128 transgenic mice displayed seizures. These findings highlight new developments for epileptogenesis prevention. Developing novel strategies to modify epileptogenesis will be effective in curing epilepsy patients. This article provides an overview of the clinical application of miRNAs as novel targets for epilepsy.

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Section: Mir-203mentioning

confidence: 99%

Section: Mir‐203mentioning

confidence: 99%

MicroRNAs and target genes in epileptogenesis

et al. 2020

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“…Functional characterization also revealed losses of function, consistent with decreased PP2A-B56(δ) functionalities in most caseseither by a dominant-negative mechanism, or by haploinsufficiency. 6 Finally, a non-sense variant in BOD1 (encoding a cellular inhibitor of PP2A-B56 complexes) was reported to cosegregate with ID in a consanguineous family, 18 and a familial reciprocal translocation (4;6)(p16.1;q22) disrupting PPP2R2C (encoding the PP2A-B55γ subunit) was associated with mild ID, epilepsy, and behavioral problems. 19 In the current study, we report on 30 additional cases (16 variants) with a de novo pathogenic variants in PPP2R1A.…”

Section: Introductionmentioning

confidence: 99%

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

Lenaerts

Reynhout

Verbinnen

et al. 2021

Genetics in Medicine

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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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“…Ki‐67, on the other hand, is a nuclear protein presented in cell cycle activity, having a direct relationship with tumour growth (Barra, 2006). Anti‐Ki‐67 antibody is one of the main markers used to assess tumour proliferative activity and is directly related to malignancy degree (Gil & Vagnarelli, 2018; Jing et al., 2019; Reynhout et al., 2019). The study of HER‐2 and Ki‐67 together has already shown benefits for a more accurate prognosis in women with breast tumours (Fasching et al., 2019), and these markers have already been used in women's ovaries (Kusamura et al., 2003; Schmoeckel et al., 2019; Sehouli et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical expression of HER ‐ 2 and Ki ‐ 67 in granulosa cell tumor in bitches

Matos

Consalter

Batista

et al. 2021

Reprod Domestic Animals

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Granulosa cell tumour, an ovarian neoplasm of stromal origin, is an important tumour related to oestrogenic dominance syndrome and cystic endometrial hyperplasia–pyometra complex. In order to analyse ovarian tumour´s malignant potential, immunohistochemical markers can be used, such as anti‐HER2 and anti‐Ki‐67. The aim of this study was to evaluate the expression of immunohistochemical markers HER‐2 and Ki‐67 in granulosa cell tumour from bitches´ ovaries. In HER‐2 immunomarker analysis using the HercepTest® method, most tumours were classified as 2+ (moderate labelling). Concerning Ki‐67 immunomarker, only one case was described as having a high proliferative index. An association was found between immunostained cell percentage by anti‐HER‐2 antibodies and high pleomorphism, represented by the pattern of follicular/trabecular tumour arrangement. There was no correlation between anti‐Ki‐67 and anti‐HER‐2 antibody immunostaining intensities, probably due to only one case with a high Ki‐67 index. With an effective protocol for HER‐2 and Ki‐67 immunohistochemical identification in granulosa cell tumours in bitches, it was possible to characterize this neoplasm proliferation profile.

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De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders

Cited by 20 publications

References 0 publications

MicroRNAs and target genes in epileptogenesis

MicroRNAs and target genes in epileptogenesis

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

Immunohistochemical expression of HER ‐ 2 and Ki ‐ 67 in granulosa cell tumor in bitches

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