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Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy
We describe a novel type of ribosomopathy that is defined by deficiency in diphthamidylation of translation elongation factor 2. The ribosomopathy was identified by correlating phenotypes and biochemical properties of previously described patients with diphthamide biosynthesis gene 1 (DPH1) deficien...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575589/ https://www.ncbi.nlm.nih.gov/pubmed/32576952 http://dx.doi.org/10.1038/s41431-020-0668-y |
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author | Hawer, Harmen Mendelsohn, Bryce A. Mayer, Klaus Kung, Ann Malhotra, Amit Tuupanen, Sari Schleit, Jennifer Brinkmann, Ulrich Schaffrath, Raffael |
author_facet | Hawer, Harmen Mendelsohn, Bryce A. Mayer, Klaus Kung, Ann Malhotra, Amit Tuupanen, Sari Schleit, Jennifer Brinkmann, Ulrich Schaffrath, Raffael |
author_sort | Hawer, Harmen |
collection | PubMed |
description | We describe a novel type of ribosomopathy that is defined by deficiency in diphthamidylation of translation elongation factor 2. The ribosomopathy was identified by correlating phenotypes and biochemical properties of previously described patients with diphthamide biosynthesis gene 1 (DPH1) deficiencies with a new patient that carried inactivating mutations in both alleles of the human diphthamide biosynthesis gene 2 (DPH2). The human DPH1 syndrome is an autosomal recessive disorder associated with developmental delay, abnormal head circumference (microcephaly or macrocephaly), short stature, and congenital heart disease. It is defined by variants with reduced functionality of the DPH1 gene observed so far predominantly in consanguineous homozygous patients carrying identical mutant alleles of DPH1. Here we report a child with a very similar phenotype carrying biallelic variants of the human DPH2. The gene products DPH1 and DPH2 are components of a heterodimeric enzyme complex that mediates the first step of the posttranslational diphthamide modification on the nonredundant eukaryotic translation elongation factor 2 (eEF2). Diphthamide deficiency was shown to reduce the accuracy of ribosomal protein biosynthesis. Both DPH2 variants described here severely impair diphthamide biosynthesis as demonstrated in human and yeast cells. This is the first report of a patient carrying compound heterozygous DPH2 loss-of-function variants with a DPH1 syndrome-like phenotype and implicates diphthamide deficiency as the root cause of this patient’s clinical phenotype as well as of DPH1-syndrome. These findings define “diphthamide-deficiency syndrome” as a special ribosomopathy due to reduced functionality of components of the cellular machinery for eEF2-diphthamide synthesis. |
format | Online Article Text |
id | pubmed-7575589 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-75755892020-10-29 Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy Hawer, Harmen Mendelsohn, Bryce A. Mayer, Klaus Kung, Ann Malhotra, Amit Tuupanen, Sari Schleit, Jennifer Brinkmann, Ulrich Schaffrath, Raffael Eur J Hum Genet Article We describe a novel type of ribosomopathy that is defined by deficiency in diphthamidylation of translation elongation factor 2. The ribosomopathy was identified by correlating phenotypes and biochemical properties of previously described patients with diphthamide biosynthesis gene 1 (DPH1) deficiencies with a new patient that carried inactivating mutations in both alleles of the human diphthamide biosynthesis gene 2 (DPH2). The human DPH1 syndrome is an autosomal recessive disorder associated with developmental delay, abnormal head circumference (microcephaly or macrocephaly), short stature, and congenital heart disease. It is defined by variants with reduced functionality of the DPH1 gene observed so far predominantly in consanguineous homozygous patients carrying identical mutant alleles of DPH1. Here we report a child with a very similar phenotype carrying biallelic variants of the human DPH2. The gene products DPH1 and DPH2 are components of a heterodimeric enzyme complex that mediates the first step of the posttranslational diphthamide modification on the nonredundant eukaryotic translation elongation factor 2 (eEF2). Diphthamide deficiency was shown to reduce the accuracy of ribosomal protein biosynthesis. Both DPH2 variants described here severely impair diphthamide biosynthesis as demonstrated in human and yeast cells. This is the first report of a patient carrying compound heterozygous DPH2 loss-of-function variants with a DPH1 syndrome-like phenotype and implicates diphthamide deficiency as the root cause of this patient’s clinical phenotype as well as of DPH1-syndrome. These findings define “diphthamide-deficiency syndrome” as a special ribosomopathy due to reduced functionality of components of the cellular machinery for eEF2-diphthamide synthesis. Springer International Publishing 2020-06-23 2020-11 /pmc/articles/PMC7575589/ /pubmed/32576952 http://dx.doi.org/10.1038/s41431-020-0668-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Hawer, Harmen Mendelsohn, Bryce A. Mayer, Klaus Kung, Ann Malhotra, Amit Tuupanen, Sari Schleit, Jennifer Brinkmann, Ulrich Schaffrath, Raffael Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy |
title | Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy |
title_full | Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy |
title_fullStr | Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy |
title_full_unstemmed | Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy |
title_short | Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy |
title_sort | diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575589/ https://www.ncbi.nlm.nih.gov/pubmed/32576952 http://dx.doi.org/10.1038/s41431-020-0668-y |
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