Journal article
Diphthamide-deficiency syndrome: a novel human developmental disorder and ribosomopathy



Publication Details
Authors:
Schaffrath, R.
Publisher:
SPRINGERNATURE
Publication year:
2020
Journal:
EUROPEAN JOURNAL OF HUMAN GENETICS
Pages range:
1497-1508
Volume number:
28
Issue number:
11
Start page:
1497
End page:
1508
Number of pages:
12
ISSN:
1018-4813

Abstract
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 humanDPH1syndrome 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 theDPH1gene observed so far predominantly in consanguineous homozygous patients carrying identical mutant alleles ofDPH1. Here we report a child with a very similar phenotype carrying biallelic variants of the humanDPH2. 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 aDPH1syndrome-like phenotype and implicates diphthamide deficiency as the root cause of this patient's clinical phenotype as well as ofDPH1-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.

Last updated on 2021-19-01 at 15:35