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.
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.
Genet Med. 2022 Jul;24(7):1567-1582. doi: 10.1016/j.gim.2022.03.014. Epub 2022 Apr 28.
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).
Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5/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.
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.
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.
二氢尿嘧啶是一种翻译后修饰的组氨酸，对信使 RNA 翻译和核糖体蛋白合成至关重要。我们提出了 DPH5 作为一种新的胚胎致死和严重神经发育迟缓（NDD）原因的证据。
使用外显子组或基因组测序进行分子检测。针对在 1 个家庭中发现的 DPH5 p.His260Arg 纯合变体，创建了靶向 Dph5 敲入小鼠（C57BL/6Ncrl-Dph5/Mmucd）。在 DPH5 敲除的人类和酵母细胞中进行二磷酸腺苷核糖基化测定，并对鉴定出的 DPH5 潜在致病性变体进行计算机建模。
在 3 个具有不同重叠颅面特征、严重 NDD、多系统异常和流产的无关家庭中，发现了 DPH5 变体 p.His260Arg（纯合子）、p.Asn110Ser 和 p.Arg207Ter（杂合子）以及 p.Asn174LysfsTer10（纯合子）。Dph5 p.His260Arg 纯合敲入是胚胎致死的，只有 1 只亚致死小鼠表现出生长受损、颅面畸形和多系统功能障碍，重现了人类表型。二磷酸腺苷核糖基化测定显示 DPH5 敲除的人类和酵母细胞中功能缺失或减少。变体的计算机建模表明 DPH5 结构发生改变，其与 eEF2 的相互作用被破坏。
我们提供了强有力的临床、生化和功能证据，证明 DPH5 是一种新的胚胎致死或严重 NDD 的原因，涉及多系统受累，并扩展了二氢尿嘧啶缺乏症和核糖体病。
