Clinical and molecular analysis of a novel variant in heme oxygenase-1 deficiency: Unraveling its role in inflammation, heme metabolism, and pulmonary phenotype.
| Autor: | Berendes LS; University of Münster, Department of General Pediatrics, Münster, Germany., Westhoff PS; University of Münster, Department of General Pediatrics, Münster, Germany., Wittkowski H; University of Münster, Department of Pediatric Rheumatology and Immunology, Münster, Germany., Seelhöfer A; University of Münster, Department of General Pediatrics, Münster, Germany., Varga G; University of Münster, Department of Pediatric Rheumatology and Immunology, Münster, Germany., Marquardt T; University of Münster, Department of General Pediatrics, Münster, Germany., Park JH; University of Münster, Department of General Pediatrics, Münster, Germany. |
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| Jazyk: | angličtina |
| Zdroj: | Molecular genetics and metabolism reports [Mol Genet Metab Rep] 2023 Dec 15; Vol. 38, pp. 101038. Date of Electronic Publication: 2023 Dec 15 (Print Publication: 2024). |
| DOI: | 10.1016/j.ymgmr.2023.101038 |
| Abstrakt: | Heme oxygenase 1 (HO-1) is the pivotal catalyst for the primary and rate-determining step in heme catabolism, playing a crucial role in mitigating heme-induced oxidative damage. Pathogenic variants in the HMOX1 gene which encodes HO-1, are responsible for a severe, multisystem disease characterized by recurrent inflammatory episodes, organ failure, and an ultimately fatal course. Chronic hemolysis and abnormally low bilirubin levels are cardinal laboratory features of this disorder. In this study, we describe a patient with severe interstitial lung disease, frequent episodes of hyperinflammation non-responsive to immunosuppression, and fatal pulmonary hemorrhage. Employing exome sequencing, we identified two protein truncating variants in HMOX1 , c.262_268delinsCC (p.Ala88Profs*51) and a previously unreported variant, c.55dupG (p.Glu19Glyfs*14). Functional analysis in patient-derived lymphoblastoid cells unveiled the complete absence of HO-1 protein expression and a marked reduction in cell viability upon exposure to hemin. These findings confirm the pathogenicity of the identified HMOX1 variants, further underscoring their association with severe pulmonary manifestations . This study describes the profound clinical consequences stemming from disruptions in redox metabolism. Competing Interests: The authors have no conflicts of interest to disclose. (© 2023 The Authors.) |
| Databáze: | MEDLINE |
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