Functional characterisation of missense ceruloplasmin variants and real-world prevalence assessment of Aceruloplasminemia using population dataResearch in context
Summary: Background: Aceruloplasminemia (ACP) is a rare recessive disease caused by loss of ceruloplasmin activity due to pathogenic variants in the ceruloplasmin (CP) gene. ACP causes iron accumulation in various organs, leading to neurodegeneration, anaemia, and diabetes. Estimating ACP prevalenc...
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Elsevier
2025-03-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396425000696 |
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| author | Nicole Ziliotto Sara Lencioni Martina Cirinciani Alan Zanardi Massimo Alessio Giulia Soldà Eleonora Da Pozzo Rosanna Asselta Andrea Caricasole |
| author_facet | Nicole Ziliotto Sara Lencioni Martina Cirinciani Alan Zanardi Massimo Alessio Giulia Soldà Eleonora Da Pozzo Rosanna Asselta Andrea Caricasole |
| author_sort | Nicole Ziliotto |
| collection | DOAJ |
| description | Summary: Background: Aceruloplasminemia (ACP) is a rare recessive disease caused by loss of ceruloplasmin activity due to pathogenic variants in the ceruloplasmin (CP) gene. ACP causes iron accumulation in various organs, leading to neurodegeneration, anaemia, and diabetes. Estimating ACP prevalence is challenging, particularly as missense variants are not readily identified as pathogenic. Methods: Heterozygous missense variants likely to impact function were mapped in gnomAD and representative examples analysed for effects on CP activity. This knowledge was complemented by prediction of destabilizing effects of potentially pathogenic missense variants and integrated with loss-of-function mutations. Global ACP prevalence was predicted and compared with a more traditional method. Findings: Several as yet uncharacterised missense CP variants of pathogenic interest were identified by structure-function in-silico analysis. A representative subset was functionally validated, together with known ACP missense variants. Insights on the relative importance of copper ions coordinating centres in CP and its substrate specificity were discovered. Overall, a destabilizing effect was predicted for 130 missense CP variants. This information, integrated with known ACP missense and loss-of-function CP variants in gnomAD, allowed an estimation of ACP prevalence of 12.6/106. An alternative analysis based on minor allele frequency ≤0.01 resulted in an ACP prevalence as high as 8/106. Interpretation: These prevalence estimates for ACP are 20–25-fold higher than previously estimated and underscore the applicability of structure-function based analyses of real-world genetic variability to provide an alternative method for representing the frequency of rare disease variants. Funding: REACT-EU PON 2014–2021, Kedrion S.p.A. |
| format | Article |
| id | doaj-art-ba57ba5eba02461a898d979f5e45b0ba |
| institution | DOAJ |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj-art-ba57ba5eba02461a898d979f5e45b0ba2025-08-20T03:16:26ZengElsevierEBioMedicine2352-39642025-03-0111310562510.1016/j.ebiom.2025.105625Functional characterisation of missense ceruloplasmin variants and real-world prevalence assessment of Aceruloplasminemia using population dataResearch in contextNicole Ziliotto0Sara Lencioni1Martina Cirinciani2Alan Zanardi3Massimo Alessio4Giulia Soldà5Eleonora Da Pozzo6Rosanna Asselta7Andrea Caricasole8Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, ItalyDepartment of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy; Department of Research & Innovation, Kedrion Biopharma S.p.A, Via di Fondovalle, Loc. Bolognana, Gallicano 55027, ItalyDepartment of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, ItalyProteome Biochemistry, COSR-Centre for Omics Sciences, IRCCS Ospedale San Raffaele, Via Olgettina 60, Milano 20132, ItalyProteome Biochemistry, COSR-Centre for Omics Sciences, IRCCS Ospedale San Raffaele, Via Olgettina 60, Milano 20132, ItalyDepartment of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072, Italy; IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano 20089, ItalyDepartment of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, ItalyDepartment of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072, Italy; IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano 20089, ItalyDepartment of Research & Innovation, Kedrion Biopharma S.p.A, Via di Fondovalle, Loc. Bolognana, Gallicano 55027, Italy; Corresponding author. Kedrion Biopharma S.p.A, Gallicano, Italy.Summary: Background: Aceruloplasminemia (ACP) is a rare recessive disease caused by loss of ceruloplasmin activity due to pathogenic variants in the ceruloplasmin (CP) gene. ACP causes iron accumulation in various organs, leading to neurodegeneration, anaemia, and diabetes. Estimating ACP prevalence is challenging, particularly as missense variants are not readily identified as pathogenic. Methods: Heterozygous missense variants likely to impact function were mapped in gnomAD and representative examples analysed for effects on CP activity. This knowledge was complemented by prediction of destabilizing effects of potentially pathogenic missense variants and integrated with loss-of-function mutations. Global ACP prevalence was predicted and compared with a more traditional method. Findings: Several as yet uncharacterised missense CP variants of pathogenic interest were identified by structure-function in-silico analysis. A representative subset was functionally validated, together with known ACP missense variants. Insights on the relative importance of copper ions coordinating centres in CP and its substrate specificity were discovered. Overall, a destabilizing effect was predicted for 130 missense CP variants. This information, integrated with known ACP missense and loss-of-function CP variants in gnomAD, allowed an estimation of ACP prevalence of 12.6/106. An alternative analysis based on minor allele frequency ≤0.01 resulted in an ACP prevalence as high as 8/106. Interpretation: These prevalence estimates for ACP are 20–25-fold higher than previously estimated and underscore the applicability of structure-function based analyses of real-world genetic variability to provide an alternative method for representing the frequency of rare disease variants. Funding: REACT-EU PON 2014–2021, Kedrion S.p.A.http://www.sciencedirect.com/science/article/pii/S2352396425000696AceruloplasminemiaCeruloplasminGenetic prevalenceFunctional analysisRare disease |
| spellingShingle | Nicole Ziliotto Sara Lencioni Martina Cirinciani Alan Zanardi Massimo Alessio Giulia Soldà Eleonora Da Pozzo Rosanna Asselta Andrea Caricasole Functional characterisation of missense ceruloplasmin variants and real-world prevalence assessment of Aceruloplasminemia using population dataResearch in context EBioMedicine Aceruloplasminemia Ceruloplasmin Genetic prevalence Functional analysis Rare disease |
| title | Functional characterisation of missense ceruloplasmin variants and real-world prevalence assessment of Aceruloplasminemia using population dataResearch in context |
| title_full | Functional characterisation of missense ceruloplasmin variants and real-world prevalence assessment of Aceruloplasminemia using population dataResearch in context |
| title_fullStr | Functional characterisation of missense ceruloplasmin variants and real-world prevalence assessment of Aceruloplasminemia using population dataResearch in context |
| title_full_unstemmed | Functional characterisation of missense ceruloplasmin variants and real-world prevalence assessment of Aceruloplasminemia using population dataResearch in context |
| title_short | Functional characterisation of missense ceruloplasmin variants and real-world prevalence assessment of Aceruloplasminemia using population dataResearch in context |
| title_sort | functional characterisation of missense ceruloplasmin variants and real world prevalence assessment of aceruloplasminemia using population dataresearch in context |
| topic | Aceruloplasminemia Ceruloplasmin Genetic prevalence Functional analysis Rare disease |
| url | http://www.sciencedirect.com/science/article/pii/S2352396425000696 |
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