Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy
We identified two unstable variants in the third exon of α-globin genes: Hb Bernalda/Groene Hart (HBA1:c.358C>T), and Hb Caserta (HBA2:c.79G>A) in <i>cis</i> to Hb Sun Prairie (HBA2:c.391G>C), also named Hb Southern Italy. These mutations occurred in the H helix of the α-globin...
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MDPI AG
2020-07-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/11/8/870 |
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| author | Giovanna Cardiero Gennaro Musollino Maria Grazia Friscia Rosario Testa Lucrezia Virruso Caterina Di Girgenti Mercedes Caldora Rosario Colella Bisogno Carlo Gaudiano Giuseppe Manco Giuseppina Lacerra |
| author_facet | Giovanna Cardiero Gennaro Musollino Maria Grazia Friscia Rosario Testa Lucrezia Virruso Caterina Di Girgenti Mercedes Caldora Rosario Colella Bisogno Carlo Gaudiano Giuseppe Manco Giuseppina Lacerra |
| author_sort | Giovanna Cardiero |
| collection | DOAJ |
| description | We identified two unstable variants in the third exon of α-globin genes: Hb Bernalda/Groene Hart (HBA1:c.358C>T), and Hb Caserta (HBA2:c.79G>A) in <i>cis</i> to Hb Sun Prairie (HBA2:c.391G>C), also named Hb Southern Italy. These mutations occurred in the H helix of the α-globin that is involved in heme contacting, specific recognition of α-hemoglobin-stabilizing protein (AHSP), and α<sub>1</sub>β<sub>1</sub> interactions. The carriers showed α-thalassemia phenotype, but one also jaundice and cholelithiasis. Molecular identification of clusters of families in Southern Italy encouraged molecular characterization of mRNA, globin chain analyses, molecular modeling studies, and comparison with globin variants to understand the mechanisms causing the α-thalassemia phenotype. A normal amount of Hb Bernalda/Groene Hart mRNA were found, and molecular modeling highlighted additional H bonds with AHSP. For Hb Southern Italy, showing an unexpected α/β biosynthetic ratio typical of the β-thalassemia type, two different molecular mechanisms were shown: Reduction of the variant mRNA, likely due to the No-Go Decay for the presence of unused triplet ACG at cod 26, and protein instability due to the impairment of AHSP interaction. The UDP glucuronosyltransferase 1A (UGT1A1) genotyping was conclusive in the case of jaundice and cholelithiasis. Multiple approaches are needed to properly identify the mechanisms leading to unstable variants and the effect of a mutation. |
| first_indexed | 2024-03-10T18:03:47Z |
| format | Article |
| id | doaj.art-07106e0e50d745dd827bd0ce9ec9e710 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T18:03:47Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-07106e0e50d745dd827bd0ce9ec9e7102023-11-20T08:39:50ZengMDPI AGGenes2073-44252020-07-0111887010.3390/genes11080870Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern ItalyGiovanna Cardiero0Gennaro Musollino1Maria Grazia Friscia2Rosario Testa3Lucrezia Virruso4Caterina Di Girgenti5Mercedes Caldora6Rosario Colella Bisogno7Carlo Gaudiano8Giuseppe Manco9Giuseppina Lacerra10Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, (IGB-ABT, CNR), National Research Council, 80131 Naples, ItalyInstitute of Genetics and Biophysics “Adriano Buzzati Traverso”, (IGB-ABT, CNR), National Research Council, 80131 Naples, ItalyAzienda Ospedaliera Ospedali Civili Riuniti, Centro Trasfusionale e di Microcitemia, 92019 Sciacca, ItalyAzienda Ospedaliero-Universitaria “Policlinico-Vittorio Emanuele”, Servizio di Talassemia ed Emoglobinopatie, 95123 Catania, ItalyARNAS P.O. Civico e Di Cristina Benfratelli, U.O.s.d. Lab. Spec. Genetica Molecolare, 90127 Palermo, ItalyARNAS P.O. Civico e Di Cristina Benfratelli, U.O.s.d. Lab. Spec. Genetica Molecolare, 90127 Palermo, ItalyP.O. Pellegrini A.S.L. Napoli1centro, 80135 Napoli, ItalyAzienda Ospedaliera Universitaria OO. RR. San Giovanni di Dio e Ruggi D’Aragona, Medicina Trasfusionale, 84131 Salerno, ItalyP.O. Madonna delle Grazie, Centro per la Lotta Contro le Microcitemie, ASL 4, 75100 Matera, ItalyInstitute of Biochemistry and Cell Biology (IBBC, CNR), National Research Council, 80131 Naples, ItalyInstitute of Genetics and Biophysics “Adriano Buzzati Traverso”, (IGB-ABT, CNR), National Research Council, 80131 Naples, ItalyWe identified two unstable variants in the third exon of α-globin genes: Hb Bernalda/Groene Hart (HBA1:c.358C>T), and Hb Caserta (HBA2:c.79G>A) in <i>cis</i> to Hb Sun Prairie (HBA2:c.391G>C), also named Hb Southern Italy. These mutations occurred in the H helix of the α-globin that is involved in heme contacting, specific recognition of α-hemoglobin-stabilizing protein (AHSP), and α<sub>1</sub>β<sub>1</sub> interactions. The carriers showed α-thalassemia phenotype, but one also jaundice and cholelithiasis. Molecular identification of clusters of families in Southern Italy encouraged molecular characterization of mRNA, globin chain analyses, molecular modeling studies, and comparison with globin variants to understand the mechanisms causing the α-thalassemia phenotype. A normal amount of Hb Bernalda/Groene Hart mRNA were found, and molecular modeling highlighted additional H bonds with AHSP. For Hb Southern Italy, showing an unexpected α/β biosynthetic ratio typical of the β-thalassemia type, two different molecular mechanisms were shown: Reduction of the variant mRNA, likely due to the No-Go Decay for the presence of unused triplet ACG at cod 26, and protein instability due to the impairment of AHSP interaction. The UDP glucuronosyltransferase 1A (UGT1A1) genotyping was conclusive in the case of jaundice and cholelithiasis. Multiple approaches are needed to properly identify the mechanisms leading to unstable variants and the effect of a mutation.https://www.mdpi.com/2073-4425/11/8/870human α-hemoglobinα-thalassemiaunstable α-Hb variantsmolecular chaperone AHSPmolecular modelingmRNA quality control |
| spellingShingle | Giovanna Cardiero Gennaro Musollino Maria Grazia Friscia Rosario Testa Lucrezia Virruso Caterina Di Girgenti Mercedes Caldora Rosario Colella Bisogno Carlo Gaudiano Giuseppe Manco Giuseppina Lacerra Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy Genes human α-hemoglobin α-thalassemia unstable α-Hb variants molecular chaperone AHSP molecular modeling mRNA quality control |
| title | Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy |
| title_full | Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy |
| title_fullStr | Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy |
| title_full_unstemmed | Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy |
| title_short | Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy |
| title_sort | effect of mutations on mrna and globin stability the cases of hb bernalda groene hart and hb southern italy |
| topic | human α-hemoglobin α-thalassemia unstable α-Hb variants molecular chaperone AHSP molecular modeling mRNA quality control |
| url | https://www.mdpi.com/2073-4425/11/8/870 |
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