A Novel DPH5-related Diphthamide-deficiency Syndrome Causing Embryonic Lethality or Profound Neurodevelopmental Disorder

Overview

Journal Genet Med

Publisher Elsevier

Specialty Genetics

Date 2022 Apr 28

PMID 35482014

Authors

Suma P Shankar

Kristin Grimsrud

Louise Lanoue

Alena Egense

Brandon Willis

Johanna Horberg

Lama AlAbdi

Klaus Mayer

Koray Utkur

Kristin G Monaghan

Joel Krier

Joan Stoler

Maha Alnemer

Prabhu R Shankar

Raffael Schaffrath

Fowzan S Alkuraya

Ulrich Brinkmann

Leif A Eriksson

Kent Lloyd

Katherine A Rauen

Affiliations

Soon will be listed here.

Abstract

Purpose: 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).

Methods: 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.

Results: 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.

Conclusion: 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.

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