Correction: DPH1 syndrome: two novel variants and structural and functional analyses of seven missense variants identified in syndromic patients

Urreizti, Roser; Mayer, K. Ulrich; Evrony, Gilad D.; Said, Edith; Castilla‐Vallmanya, Laura; Cody, Neal; Plasencia, Guillem; Gelb, Bruce D.; Grinberg, Daniel; Brinkmann, Ulrich; Webb, Bryn D.; Balcells, Susana

doi:10.1038/s41431-019-0394-5

Cited by 3 publications

(4 citation statements)

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“…Other high-confidence genes include FKBP2, which plays an important role in immunoregulation, protein folding and trafficking 56 and SYNE1, with one of its transcripts encoding CPG2, a brain-specific protein localized to excitatory postsynaptic sites, which regulates glutamate receptor internalization 57 . PLAC-seq data also prioritized genes with relevant biological functions, such as INSYN2B (inhibitory synaptic factor family member 2b), KCNQ2 (potassium voltage-gated channel subfamily Q member 2) and DPH1 (diphthamide biosynthesis 1) with variants in this gene associated with developmental delay 58 . Of the 25 high-confidence genes, CACNA1B, TRPT1, YWHAE and EEF1A2 were not the closest gene to the GWAS index SNP, and of the 22 union consensus SNPs, 8 were not the top lead SNP from the GWAS, illustrating the utility of fine-mapping.…”

Section: Discussionmentioning

confidence: 99%

Fine-mapping genomic loci refines bipolar disorder risk genes

Koromina,

Ravi,

Panagiotaropoulou

et al. 2024

Preprint

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Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

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Section: Discussionmentioning

confidence: 99%

Fine-mapping genomic loci refines bipolar disorder risk genes

Koromina,

Ravi,

Panagiotaropoulou

et al. 2024

Preprint

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“…1c−e). Although these mutations have not been reported previously, the proband was diagnosed with DEDSSH1 based on the similarities in symptoms with other patients with autosomal recessive DPH1 mutations [4][5][6][7][8] .…”

Section: A Dedssh Patient With Compound Heterozygous Mutations In Dph1mentioning

confidence: 99%

“…Hence the conserved Glu242 of eukaryotic DPH1 may play an important role in positioning Arg349 in the active site to interact with the SAM carboxyl group, and the E242Q mutation in the proband, which disrupts the Glu242-Arg349 salt bridge, leads to partial loss of DPH1 function. To examine if the other known DEDSSH-associated missense DPH1 mutations 5,6,8,13 also lead to decreased DPH1 activity, we generated DPH1-KO HEK293T cells using CRISPR-Cas9. As compared with wild-type DPH1, all tested mutants showed reduced abilities to rescue eEF2 diphthamide modification when overexpressed in DPH1-KO HEK293T cells (Supplementary Fig.…”

Section: A Dedssh Patient With Compound Heterozygous Mutations In Dph1mentioning

confidence: 99%

“…Autosomal recessive mutations in human DPH1 or DPH2 have been linked to developmental delay with short stature, dysmorphic features, and sparse hair (DEDSSH1 and DEDSSH2; OMIM 616901 and 620062, respectively), rare genetic syndromes with characteristic craniofacial disorders, growth retardation, and intellectual disability [4][5][6][7][8] . The symptoms are reminiscence of the phenotypes of DPH1 knockout (KO) mice, which are largely rescued by replacing the endogenous eEF2 with a G717R mutant that mimics diphthamidemodified eEF2 1,9,10 , suggesting that they are caused by disrupted eEF2 diphthamide modification.…”

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confidence: 99%

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Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects

Shi,

Huang,

Song

et al. 2024

Nat Commun

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Diphthamide is a modified histidine residue unique for eukaryotic translation elongation factor 2 (eEF2), a key ribosomal protein. Loss of this evolutionarily conserved modification causes developmental defects through unknown mechanisms. In a patient with compound heterozygous mutations in Diphthamide Biosynthesis 1 (DPH1) and impaired eEF2 diphthamide modification, we observe multiple defects in neural crest (NC)-derived tissues. Knockin mice harboring the patient’s mutations and Xenopus embryos with Dph1 depleted also display NC defects, which can be attributed to reduced proliferation in the neuroepithelium. DPH1 depletion facilitates dissociation of eEF2 from ribosomes and association with p53 to promote transcription of the cell cycle inhibitor p21, resulting in inhibited proliferation. Knockout of one p21 allele rescues the NC phenotypes in the knockin mice carrying the patient’s mutations. These findings uncover an unexpected role for eEF2 as a transcriptional coactivator for p53 to induce p21 expression and NC defects, which is regulated by diphthamide modification.

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