{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T11:34:31Z","timestamp":1778326471062,"version":"3.51.4"},"reference-count":41,"publisher":"The Company of Biologists","issue":"9","license":[{"start":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T00:00:00Z","timestamp":1695340800000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100012687","name":"Universit\u00e4t Kassel","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100012687","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["SPP1927: SCHA750\/21"],"award-info":[{"award-number":["SPP1927: SCHA750\/21"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Roche Diagnostics GmbH"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>The autosomal-recessive diphthamide deficiency syndrome presents as intellectual disability with developmental abnormalities, seizures, craniofacial and additional morphological phenotypes. It is caused by reduced activity of proteins that synthesize diphthamide on human translation elongation factor 2. Diphthamide synthesis requires seven proteins (DPH1-DPH7), with clinical deficiency described for DPH1, DPH2 and DPH5. A limited set of variant alleles from syndromic patients has been functionally analyzed, but databases (gnomAD) list additional so far uncharacterized variants in human DPH1 and DPH2. Because DPH enzymes are conserved among eukaryotes, their functionality can be assessed in yeast and mammalian cells. Our experimental assessment of known and uncharacterized DPH1 and DPH2 missense alleles showed that six variants are tolerated despite inter-species conservation. Ten additional human DPH1 (G113R, A114T, H132P, H132R, S136R, C137F, L138P, Y152C, S221P, H240R) and two DPH2 (H105P, C341Y) variants showed reduced functionality and hence are deficiency-susceptibility alleles. Some variants locate close to the active enzyme center and may affect catalysis, while others may impact on enzyme activation. In sum, our study has identified functionally compromised alleles of DPH1 and DPH2 genes that likely cause diphthamide deficiency syndrome.<\/jats:p>","DOI":"10.1242\/dmm.050207","type":"journal-article","created":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T08:00:42Z","timestamp":1694073642000},"source":"Crossref","is-referenced-by-count":9,"title":["DPH1 and DPH2 variants that confer susceptibility to diphthamide deficiency syndrome in human cells and yeast models"],"prefix":"10.1242","volume":"16","author":[{"given":"Koray","family":"\u00dctk\u00fcr","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Biologie, 1 Fachgebiet Mikrobiologie , 34132 Kassel , Germany"},{"name":", Universit\u00e4t Kassel 1 Fachgebiet Mikrobiologie , 34132 Kassel , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus","family":"Mayer","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich 2 , 82377 Penzberg , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maliha","family":"Khan","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Biologie, 1 Fachgebiet Mikrobiologie , 34132 Kassel , Germany"},{"name":", Universit\u00e4t Kassel 1 Fachgebiet Mikrobiologie , 34132 Kassel , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thirishika","family":"Manivannan","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Biologie, 1 Fachgebiet Mikrobiologie , 34132 Kassel , Germany"},{"name":", Universit\u00e4t Kassel 1 Fachgebiet Mikrobiologie , 34132 Kassel , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9484-5247","authenticated-orcid":false,"given":"Raffael","family":"Schaffrath","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Biologie, 1 Fachgebiet Mikrobiologie , 34132 Kassel , Germany"},{"name":", Universit\u00e4t Kassel 1 Fachgebiet Mikrobiologie , 34132 Kassel , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5558-0212","authenticated-orcid":false,"given":"Ulrich","family":"Brinkmann","sequence":"additional","affiliation":[{"name":"Roche Pharma Research and Early Development (pRED), Large Molecule Research, Roche Innovation Center Munich 2 , 82377 Penzberg , Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2023,9,22]]},"reference":[{"key":"2023092208061690700_DMM050207C1","doi-asserted-by":"publisher","first-page":"958","DOI":"10.3390\/toxins5050958","article-title":"Insights into diphthamide, key diphtheria toxin effector","volume":"5","author":"Abdel-Fattah","year":"2013","journal-title":"Toxins"},{"key":"2023092208061690700_DMM050207C2","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.celrep.2014.12.015","article-title":"Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families","volume":"10","author":"Alazami","year":"2015","journal-title":"Cell Rep."},{"key":"2023092208061690700_DMM050207C3","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.freeradbiomed.2013.10.015","article-title":"Elongation factor 2 diphthamide is critical for translation of two IRES-dependent protein targets, XIAP and FGF2, under oxidative stress conditions","volume":"67","author":"Arg\u00fcelles","year":"2014","journal-title":"Free Radic. 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