한빛사논문
- 조회149
Alban Ziegler 1, Katharina Steindl 2, Ashleigh S Hanner 3, Rajesh Kumar Kar 3, Clément Prouteau 4, Anne Boland 5, Jean Francois Deleuze 5, Christine Coubes 6, Stéphane Bézieau 7, Sébastien Küry 7, Isabelle Maystadt 8, Morgane Le Mao 9, Guy Lenaers 10, Benjamin Navet 4, Laurence Faivre 11, Frédéric Tran Mau-Them 12, Paolo Zanoni 2, Wendy K Chung 13, Anita Rauch 14, Dominique Bonneau 15, Myung Hee Park 16
1Département de Génétique Médicale, Centre Hospitalier Universitaire d'Angers, 49933, Angers France; Université d'Angers, MitoVasc Unit, UMR Centre National de la Recherche Scientifique 6015, INSERM 1083, 49000 Angers, France. Electronic address: alban.ziegler@chu-angers.fr.
2Institute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland.
3National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.
4Département de Génétique Médicale, Centre Hospitalier Universitaire d'Angers, 49933, Angers France.
5Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, 91057, Evry, France.
6Département de Génétique Médicale, Hôpital Arnaud de Villeneuve, Centre Hospitalier-Universitaire de Montpellier, 34295 Montpellier, France.
7Nantes Université, Centre Hospitalier Universitaire Nantes, Service de Génétique Médicale, 44000 Nantes, France; Nantes Université, Centre Hospitalier Universitaire Nantes, Centre National de la Recherche Scientifique, INSERM, l'institut du thorax, 44000 Nantes, France.
8Centre de Génétique Humaine, Institut de Pathologie et de Génétique, 6041 Gosselies, Belgique.
9Université d'Angers, MitoVasc Unit, UMR Centre National de la Recherche Scientifique 6015, INSERM 1083, 49000 Angers, France.
10Université d'Angers, MitoVasc Unit, UMR Centre National de la Recherche Scientifique 6015, INSERM 1083, 49000 Angers, France; Service de Neurologie, Centre Hospitalier Universitaire d'Angers, 49933, Angers France.
11Unité de Formation et de Recherche des Sciences de Santé, INSERM-Université de Bourgogne, UMR 1231, Genetics of Developmental Disorders, FHU-TRANSLAD, 21000, Dijon, France; Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU-TRANSLAD, Hôpital d'Enfants, Centre Hospitalier Universitaire Dijon, 21000, Dijon, France.
12Unité de Formation et de Recherche des Sciences de Santé, INSERM-Université de Bourgogne, UMR 1231, Genetics of Developmental Disorders, FHU-TRANSLAD, 21000, Dijon, France; Unité Fonctionnelle d'Innovation Diagnostique des Maladies Rares, FHU-TRANSLAD, Centre Hospitalier Universitaire Dijon Bourgogne, Dijon, France.
13Department of Pediatrics, Columbia University, New York, NY 10032, USA; Department of Medicine, Columbia University, New York, NY 10032, USA.
14Institute of Medical Genetics, University of Zurich, 8952 Schlieren-Zurich, Switzerland; University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
15Département de Génétique Médicale, Centre Hospitalier Universitaire d'Angers, 49933, Angers France; Université d'Angers, MitoVasc Unit, UMR Centre National de la Recherche Scientifique 6015, INSERM 1083, 49000 Angers, France.
16National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.
Corresponding authors: Alban Ziegler, Myung Hee Park
Abstract
Deoxyhypusine hydroxylase (DOHH) is the enzyme catalyzing the second step in the post-translational synthesis of hypusine [Nε-(4-amino-2-hydroxybutyl)lysine] in the eukaryotic initiation factor 5A (eIF5A). Hypusine is formed exclusively in eIF5A by two sequential enzymatic steps catalyzed by deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). Hypusinated eIF5A is essential for translation and cell proliferation in eukaryotes, and all three genes encoding eIF5A, DHPS, and DOHH are highly conserved throughout eukaryotes. Pathogenic variants affecting either DHPS or EIF5A have been previously associated with neurodevelopmental disorders. Using trio exome sequencing, we identified rare bi-allelic pathogenic missense and truncating DOHH variants segregating with disease in five affected individuals from four unrelated families. The DOHH variants are associated with a neurodevelopmental phenotype that is similar to phenotypes caused by DHPS or EIF5A variants and includes global developmental delay, intellectual disability, facial dysmorphism, and microcephaly. A two-dimensional gel analyses revealed the accumulation of deoxyhypusine-containing eIF5A [eIF5A(Dhp)] and a reduction in the hypusinated eIF5A in fibroblasts derived from affected individuals, providing biochemical evidence for deficiency of DOHH activity in cells carrying the bi-allelic DOHH variants. Our data suggest that rare bi-allelic variants in DOHH result in reduced enzyme activity, limit the hypusination of eIF5A, and thereby lead to a neurodevelopmental disorder.
논문정보
- Research article
- 2022년 08월 (BRIC 등록일 2023-03-07)
- 국외 연구진
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