Expanding the clinical spectrum of PPP3CA variants - alternative isoforms matter
Abstract Background the protein phosphatase 3 catalytic subunit alpha (PPP3CA) gene encodes for the alpha isoform of the calcineurin catalytic subunit, which controls the phosphorylation status of many targets. Currently, 23 pathogenic variants of PPP3CA are known, with clinical manifestations varyi...
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BMC
2024-12-01
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| Series: | Orphanet Journal of Rare Diseases |
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| Online Access: | https://doi.org/10.1186/s13023-024-03507-0 |
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| author | Silvia Castiglioni Laura Pezzoli Lidia Pezzani Antonella Lettieri Elisabetta Di Fede Anna Cereda Silvia Ancona Andrea Gallina Elisa Adele Colombo Chiara Parodi Paolo Grazioli Esi Taci Donatella Milani Maria Iascone Valentina Massa Cristina Gervasini |
| author_facet | Silvia Castiglioni Laura Pezzoli Lidia Pezzani Antonella Lettieri Elisabetta Di Fede Anna Cereda Silvia Ancona Andrea Gallina Elisa Adele Colombo Chiara Parodi Paolo Grazioli Esi Taci Donatella Milani Maria Iascone Valentina Massa Cristina Gervasini |
| author_sort | Silvia Castiglioni |
| collection | DOAJ |
| description | Abstract Background the protein phosphatase 3 catalytic subunit alpha (PPP3CA) gene encodes for the alpha isoform of the calcineurin catalytic subunit, which controls the phosphorylation status of many targets. Currently, 23 pathogenic variants of PPP3CA are known, with clinical manifestations varying by mutation type and domain. Results through whole exome sequencing, we found two de novo variants in PPP3CA: a frameshift variant predicted leading to a truncated protein in Pt.1 and a splicing variant in Pt.2 associated with mild phenotype. PPP3CA is ubiquitously expressed with tissue-specificity of; namely, splicing isoform 1 prevailing over isoform 2 in the central nervous system. By analyzing isoform distribution in patient-derived cell lines, we highlight a skewed expression of both isoforms in Pt.1, whereas only isoform 2 shows a moderate reduction in Pt.2. In contrast, we did not observe significant abundance changes at the protein level. Cell lines derived from Pt.1 showed a reduced proliferation, associated with an increase in cell death and the upregulation of the unfolded protein response (UPR) pathway. Conclusion data suggest that an aberrant PPP3CA protein in Pt.1 could lead to UPR activation resulting in increased cell death. In Pt.2 an imbalance between the two main isoforms possibly explains the peculiar pathological manifestations, such as a moderate developmental delay. |
| format | Article |
| id | doaj-art-e46a9e6885aa4e15898dd68b20342f01 |
| institution | OA Journals |
| issn | 1750-1172 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj-art-e46a9e6885aa4e15898dd68b20342f012025-08-20T02:31:52ZengBMCOrphanet Journal of Rare Diseases1750-11722024-12-011911910.1186/s13023-024-03507-0Expanding the clinical spectrum of PPP3CA variants - alternative isoforms matterSilvia Castiglioni0Laura Pezzoli1Lidia Pezzani2Antonella Lettieri3Elisabetta Di Fede4Anna Cereda5Silvia Ancona6Andrea Gallina7Elisa Adele Colombo8Chiara Parodi9Paolo Grazioli10Esi Taci11Donatella Milani12Maria Iascone13Valentina Massa14Cristina Gervasini15Department of Health Sciences, Università degli Studi di MilanoMedical Genetics Laboratory, Papa Giovanni XXIII HospitalPediatrics, Papa Giovanni XXIII HospitalDepartment of Health Sciences, Università degli Studi di MilanoDepartment of Health Sciences, Università degli Studi di MilanoPediatrics, Papa Giovanni XXIII HospitalDepartment of Health Sciences, Università degli Studi di MilanoDepartment of Health Sciences, Università degli Studi di MilanoDepartment of Health Sciences, Università degli Studi di MilanoDepartment of Health Sciences, Università degli Studi di MilanoDepartment of Health Sciences, Università degli Studi di MilanoDepartment of Health Sciences, Università degli Studi di MilanoFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMedical Genetics Laboratory, Papa Giovanni XXIII HospitalDepartment of Health Sciences, Università degli Studi di MilanoDepartment of Health Sciences, Università degli Studi di MilanoAbstract Background the protein phosphatase 3 catalytic subunit alpha (PPP3CA) gene encodes for the alpha isoform of the calcineurin catalytic subunit, which controls the phosphorylation status of many targets. Currently, 23 pathogenic variants of PPP3CA are known, with clinical manifestations varying by mutation type and domain. Results through whole exome sequencing, we found two de novo variants in PPP3CA: a frameshift variant predicted leading to a truncated protein in Pt.1 and a splicing variant in Pt.2 associated with mild phenotype. PPP3CA is ubiquitously expressed with tissue-specificity of; namely, splicing isoform 1 prevailing over isoform 2 in the central nervous system. By analyzing isoform distribution in patient-derived cell lines, we highlight a skewed expression of both isoforms in Pt.1, whereas only isoform 2 shows a moderate reduction in Pt.2. In contrast, we did not observe significant abundance changes at the protein level. Cell lines derived from Pt.1 showed a reduced proliferation, associated with an increase in cell death and the upregulation of the unfolded protein response (UPR) pathway. Conclusion data suggest that an aberrant PPP3CA protein in Pt.1 could lead to UPR activation resulting in increased cell death. In Pt.2 an imbalance between the two main isoforms possibly explains the peculiar pathological manifestations, such as a moderate developmental delay.https://doi.org/10.1186/s13023-024-03507-0PPP3CAcalcineurinDEE-91LCLsUPS |
| spellingShingle | Silvia Castiglioni Laura Pezzoli Lidia Pezzani Antonella Lettieri Elisabetta Di Fede Anna Cereda Silvia Ancona Andrea Gallina Elisa Adele Colombo Chiara Parodi Paolo Grazioli Esi Taci Donatella Milani Maria Iascone Valentina Massa Cristina Gervasini Expanding the clinical spectrum of PPP3CA variants - alternative isoforms matter Orphanet Journal of Rare Diseases PPP3CA calcineurin DEE-91 LCLs UPS |
| title | Expanding the clinical spectrum of PPP3CA variants - alternative isoforms matter |
| title_full | Expanding the clinical spectrum of PPP3CA variants - alternative isoforms matter |
| title_fullStr | Expanding the clinical spectrum of PPP3CA variants - alternative isoforms matter |
| title_full_unstemmed | Expanding the clinical spectrum of PPP3CA variants - alternative isoforms matter |
| title_short | Expanding the clinical spectrum of PPP3CA variants - alternative isoforms matter |
| title_sort | expanding the clinical spectrum of ppp3ca variants alternative isoforms matter |
| topic | PPP3CA calcineurin DEE-91 LCLs UPS |
| url | https://doi.org/10.1186/s13023-024-03507-0 |
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