Suma P Shankar1, Kristin Grimsrud2, Louise Lanoue3, Alena Egense4, Brandon Willis3, Johanna Hörberg5, Lama AlAbdi6, Klaus Mayer7, Koray Ütkür8, Kristin G Monaghan9, Joel Krier10, Joan Stoler11, Maha Alnemer12, Prabhu R Shankar13, Raffael Schaffrath8, Fowzan S Alkuraya14, Ulrich Brinkmann7, Leif A Eriksson5, Kent Lloyd15, Katherine A Rauen4. 1. Division of Genomic Medicine, UC Davis Health MIND Institute, Department of Pediatrics, UC Davis Health, University of California, Davis, Sacramento, CA; Department of Ophthalmology and Vision Science, UC Davis Health, University of California, Davis, Sacramento, CA. Electronic address: spshankar@ucdavis.edu. 2. Department of Pathology and Laboratory Medicine, UC Davis Health, University of California, Davis, Sacramento, CA; UC Davis Mouse Biology Program, University of California, Davis, Davis, CA. 3. UC Davis Mouse Biology Program, University of California, Davis, Davis, CA. 4. Division of Genomic Medicine, UC Davis Health MIND Institute, Department of Pediatrics, UC Davis Health, University of California, Davis, Sacramento, CA. 5. Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden. 6. Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 7. Roche Pharma Research and Early Development (pRED), Roche Innovation Center Munich (RICM), Penzberg, Germany. 8. Division of Microbiology, Institute of Biology, University of Kassel, Kassel, Germany. 9. GeneDx, Gaithersburg, MD. 10. Division of Genetics, Brigham and Women's Hospital, Boston, MA; Undiagnosed Diseases Network. 11. Undiagnosed Diseases Network; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA. 12. Department of Obstetrics & Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 13. Division of Health Informatics, Department of Public Health Sciences, School of Medicine, University of California, Davis, Sacramento, CA. 14. Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 15. UC Davis Mouse Biology Program, University of California, Davis, Davis, CA; Department of Surgery, UC Davis Health, University of California, Davis, Sacramento, CA.
Abstract
PURPOSE: Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs). METHODS: Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants. RESULTS: DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2. CONCLUSION: We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.
PURPOSE: Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs). METHODS: Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5em1Mbp/Mmucd) was created for a DPH5 p.His260Arg homozygous variant identified in 1 family. Adenosine diphosphate-ribosylation assays in DPH5-knockout human and yeast cells and in silico modeling were performed for the identified DPH5 potential pathogenic variants. RESULTS: DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2. CONCLUSION: We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.
Authors: Roser Urreizti; Klaus Mayer; Gilad D Evrony; Ulrich Brinkmann; Bryn D Webb; Susanna Balcells; Edith Said; Laura Castilla-Vallmanya; Neal A L Cody; Guillem Plasencia; Bruce D Gelb; Daniel Grinberg Journal: Eur J Hum Genet Date: 2019-03-15 Impact factor: 4.246
Authors: Peter J Thul; Lovisa Åkesson; Mikaela Wiking; Diana Mahdessian; Aikaterini Geladaki; Hammou Ait Blal; Tove Alm; Anna Asplund; Lars Björk; Lisa M Breckels; Anna Bäckström; Frida Danielsson; Linn Fagerberg; Jenny Fall; Laurent Gatto; Christian Gnann; Sophia Hober; Martin Hjelmare; Fredric Johansson; Sunjae Lee; Cecilia Lindskog; Jan Mulder; Claire M Mulvey; Peter Nilsson; Per Oksvold; Johan Rockberg; Rutger Schutten; Jochen M Schwenk; Åsa Sivertsson; Evelina Sjöstedt; Marie Skogs; Charlotte Stadler; Devin P Sullivan; Hanna Tegel; Casper Winsnes; Cheng Zhang; Martin Zwahlen; Adil Mardinoglu; Fredrik Pontén; Kalle von Feilitzen; Kathryn S Lilley; Mathias Uhlén; Emma Lundberg Journal: Science Date: 2017-05-11 Impact factor: 47.728
Authors: Shanow Uthman; Christian Bär; Viktor Scheidt; Shihui Liu; Sara ten Have; Flaviano Giorgini; Michael J R Stark; Raffael Schaffrath Journal: PLoS Genet Date: 2013-02-28 Impact factor: 5.917