Characterization of Two Cases of Congenital Dyserythropoietic Anemia Type I Shed Light on the Uncharacterized C15orf41 Protein
CDA type I is a rare hereditary anemia, characterized by relative reticulocytopenia, and congenital anomalies. It is caused by biallelic mutations in one of the two genes: (i) CDAN1, encoding Codanin-1, which is implicated in nucleosome assembly and disassembly; (ii) C15orf41, which is predicted to...
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| Format: | Article |
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Frontiers Media S.A.
2019-05-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2019.00621/full |
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| author | Roberta Russo Roberta Russo Roberta Marra Roberta Marra Immacolata Andolfo Immacolata Andolfo Gianluca De Rosa Gianluca De Rosa Barbara Eleni Rosato Barbara Eleni Rosato Francesco Manna Antonella Gambale Antonella Gambale Maddalena Raia Sule Unal Susanna Barella Achille Iolascon Achille Iolascon |
| author_facet | Roberta Russo Roberta Russo Roberta Marra Roberta Marra Immacolata Andolfo Immacolata Andolfo Gianluca De Rosa Gianluca De Rosa Barbara Eleni Rosato Barbara Eleni Rosato Francesco Manna Antonella Gambale Antonella Gambale Maddalena Raia Sule Unal Susanna Barella Achille Iolascon Achille Iolascon |
| author_sort | Roberta Russo |
| collection | DOAJ |
| description | CDA type I is a rare hereditary anemia, characterized by relative reticulocytopenia, and congenital anomalies. It is caused by biallelic mutations in one of the two genes: (i) CDAN1, encoding Codanin-1, which is implicated in nucleosome assembly and disassembly; (ii) C15orf41, which is predicted to encode a divalent metal ion-dependent restriction endonuclease with a yet unknown function. We described two cases of CDA type I, identifying the novel variant, Y94S, in the DNA binding domain of C15orf41, and the H230P mutation in the nuclease domain of the protein. We first analyzed the gene expression and the localization of C15orf41. We demonstrated that C15orf41 and CDAN1 gene expression is tightly correlated, suggesting a shared mechanism of regulation between the two genes. Moreover, we functionally characterized the two variants, establishing that the H230P leads to reduced gene expression and protein level, while Y94S induces a slight decrease of expression. We demonstrated that C15orf41 endogenous protein exhibits nuclear and cytosolic localization, being mostly in the nucleus. However, no altered nuclear-cytosolic compartmentalization of mutated C15orf41 was observed. Both mutants accounted for impaired erythroid differentiation in K562 cells, and H230P mutant also exhibits an increased S-phase of the cell cycle in these cells. Our functional characterization demonstrated that the two variants have different effects on the stability of the mutated mRNA, but both resulted in impaired erythroid maturation, suggesting the block of cell cycle dynamics as a putative pathogenic mechanism for C15orf41-related CDA I. |
| first_indexed | 2024-12-23T21:22:23Z |
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| id | doaj.art-225bebeceeda4bfc9ee13256f0cfb5b6 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-23T21:22:23Z |
| publishDate | 2019-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Physiology |
| spelling | doaj.art-225bebeceeda4bfc9ee13256f0cfb5b62022-12-21T17:30:43ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2019-05-011010.3389/fphys.2019.00621438553Characterization of Two Cases of Congenital Dyserythropoietic Anemia Type I Shed Light on the Uncharacterized C15orf41 ProteinRoberta Russo0Roberta Russo1Roberta Marra2Roberta Marra3Immacolata Andolfo4Immacolata Andolfo5Gianluca De Rosa6Gianluca De Rosa7Barbara Eleni Rosato8Barbara Eleni Rosato9Francesco Manna10Antonella Gambale11Antonella Gambale12Maddalena Raia13Sule Unal14Susanna Barella15Achille Iolascon16Achille Iolascon17Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, ItalyCEINGE Biotecnologie Avanzate, Naples, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, ItalyCEINGE Biotecnologie Avanzate, Naples, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, ItalyCEINGE Biotecnologie Avanzate, Naples, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, ItalyCEINGE Biotecnologie Avanzate, Naples, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, ItalyCEINGE Biotecnologie Avanzate, Naples, ItalyCEINGE Biotecnologie Avanzate, Naples, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, ItalyCEINGE Biotecnologie Avanzate, Naples, ItalyCEINGE Biotecnologie Avanzate, Naples, ItalyDivision of Pediatric Hematology, Hacettepe University, Ankara, TurkeySSD Talassemie, Anemie Rare e Dismetabolismi del Ferro, Ospedale Pediatrico Microcitemico Antonio Cao, Azienda Ospedaliera Brotzu, Cagliari, ItalyDipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, ItalyCEINGE Biotecnologie Avanzate, Naples, ItalyCDA type I is a rare hereditary anemia, characterized by relative reticulocytopenia, and congenital anomalies. It is caused by biallelic mutations in one of the two genes: (i) CDAN1, encoding Codanin-1, which is implicated in nucleosome assembly and disassembly; (ii) C15orf41, which is predicted to encode a divalent metal ion-dependent restriction endonuclease with a yet unknown function. We described two cases of CDA type I, identifying the novel variant, Y94S, in the DNA binding domain of C15orf41, and the H230P mutation in the nuclease domain of the protein. We first analyzed the gene expression and the localization of C15orf41. We demonstrated that C15orf41 and CDAN1 gene expression is tightly correlated, suggesting a shared mechanism of regulation between the two genes. Moreover, we functionally characterized the two variants, establishing that the H230P leads to reduced gene expression and protein level, while Y94S induces a slight decrease of expression. We demonstrated that C15orf41 endogenous protein exhibits nuclear and cytosolic localization, being mostly in the nucleus. However, no altered nuclear-cytosolic compartmentalization of mutated C15orf41 was observed. Both mutants accounted for impaired erythroid differentiation in K562 cells, and H230P mutant also exhibits an increased S-phase of the cell cycle in these cells. Our functional characterization demonstrated that the two variants have different effects on the stability of the mutated mRNA, but both resulted in impaired erythroid maturation, suggesting the block of cell cycle dynamics as a putative pathogenic mechanism for C15orf41-related CDA I.https://www.frontiersin.org/article/10.3389/fphys.2019.00621/fullCDA (I–III)C15ORF41functional characterization of proteinsgenetic testinganemia |
| spellingShingle | Roberta Russo Roberta Russo Roberta Marra Roberta Marra Immacolata Andolfo Immacolata Andolfo Gianluca De Rosa Gianluca De Rosa Barbara Eleni Rosato Barbara Eleni Rosato Francesco Manna Antonella Gambale Antonella Gambale Maddalena Raia Sule Unal Susanna Barella Achille Iolascon Achille Iolascon Characterization of Two Cases of Congenital Dyserythropoietic Anemia Type I Shed Light on the Uncharacterized C15orf41 Protein Frontiers in Physiology CDA (I–III) C15ORF41 functional characterization of proteins genetic testing anemia |
| title | Characterization of Two Cases of Congenital Dyserythropoietic Anemia Type I Shed Light on the Uncharacterized C15orf41 Protein |
| title_full | Characterization of Two Cases of Congenital Dyserythropoietic Anemia Type I Shed Light on the Uncharacterized C15orf41 Protein |
| title_fullStr | Characterization of Two Cases of Congenital Dyserythropoietic Anemia Type I Shed Light on the Uncharacterized C15orf41 Protein |
| title_full_unstemmed | Characterization of Two Cases of Congenital Dyserythropoietic Anemia Type I Shed Light on the Uncharacterized C15orf41 Protein |
| title_short | Characterization of Two Cases of Congenital Dyserythropoietic Anemia Type I Shed Light on the Uncharacterized C15orf41 Protein |
| title_sort | characterization of two cases of congenital dyserythropoietic anemia type i shed light on the uncharacterized c15orf41 protein |
| topic | CDA (I–III) C15ORF41 functional characterization of proteins genetic testing anemia |
| url | https://www.frontiersin.org/article/10.3389/fphys.2019.00621/full |
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