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.

我们描述了一种新型核糖体病，其定义为翻译延伸因子 2 的二苯甲酰化缺陷。核糖体病是通过将先前描述的二苯甲酰胺生物合成基因 1 ( DPH1 ) 缺陷患者的表型和生化特性与携带失活基因的新患者相关联来鉴定的。人类二邻苯二甲酰胺生物合成基因 2 ( DPH2 ) 的两个等位基因均发生突变。人类DPH1综合征是一种常染色体隐性遗传疾病，与发育迟缓、头围异常（小头畸形或大头畸形）、身材矮小和先天性心脏病相关。它是由迄今为止观察到的DPH1基因功能降低的变体定义的，这些变体主要在携带相同DPH1突变等位基因的近亲纯合患者中观察到。在这里，我们报告了一个具有非常相似表型的儿童，携带人类DPH2的双等位基因变体。基因产物 DPH1 和 DPH2 是异二聚酶复合物的组成部分，该复合物介导非冗余真核翻译延伸因子 2 (eEF2) 上翻译后二邻酰胺修饰的第一步。研究表明，二苯胺缺乏会降低核糖体蛋白质生物合成的准确性。这里描述的两种 DPH2 变体都会严重损害二邻苯二甲酰胺的生物合成，正如在人类和酵母细胞中所证明的那样。这是首例携带复合杂合 DPH2 功能丧失变异体且具有DPH1综合征样表型的患者的报告，表明苯妥英缺乏症是该患者临床表型以及DPH1综合征的根本原因。这些发现将“二邻苯二甲酰胺缺乏综合征”定义为一种特殊的核糖体病，其原因是 eEF2-二邻苯二甲酰胺合成的细胞机制功能降低。