PubMed · 334318
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G V Born. 1977. Fluid-mechanical and biochemical interactions in haemostasis.. https://doi.org/10.1093/oxfordjournals.bmb.a071435
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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-Dph5em1Mbp/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.
Addition of N-acetyl neuraminic acid (sialic acid, NANA) to citrated rat platelet-rich plasma significantly inhibited aggregation induced by near-threshold concentration of ADP, collagen or thrombin. In heparinized rat platelet-rich plasma aggregation of platelets induced by endotoxin or tumour cells of various origins was also inhibited by sialic acid. It is suggested that exogenous or endogenous sialic acid may act against various aggregating stimuli on the platelet membrane by masking a common factor through which various aggregating agents exert their effect.
The role of reduced glutathione (GSH) on platelet functions was investigated utilizing thiol oxidizing agent, "diamide". Diamide reacted rapidly with GSH in platelets, but not with protein thiols. Platelets treated with diamide showed inhibition of platelet aggregation induced by ADP, epinephrine and collagen in a concentration dependent manner. Clot retraction was grossly inhibited by diamide. Platelet interaction with polymerizing fibrin was examined by the method of Niewiarowski et al. (1972). There was no interaction obeserved between diamide-treated platelets and polymerizing fibrin. Ultrastructural observation of clots formed in the presence of diamide also showed no direct contact between platelets and fibrin strands. Platelets retained their granular contents, but showed loss of microtubules and dilatation of open canalicular system. Our findings may further support the idea that GSH plays an important role on platelet functions.