PubMed · 3529484
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T Lecompte, C Lecrubier, F Potevin, M Samama. 1986-06-30. Ticlopidine and platelet function.. https://pubmed.ncbi.nlm.nih.gov/3529484/
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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.
Hypoxia-ischemia and ATP depletion are associated with glial swelling and blebbing, but mechanisms involved in these effects remain incompletely characterized. We examined morphological and electrophysiological responses of freshly isolated native reactive astrocytes (NRAs) after exposure to NaN(3), which depletes cellular ATP. Here we report that NaN(3) caused profound and sustained depolarization attributable to activation of a novel 35 pS Ca(2+)-activated, [ATP](i)-sensitive nonselective cation (NC(Ca-ATP)) channel, found in >90% of excised membrane patches. The channel was impermeable to Cl(-), was nearly equally permeable to monovalent cations, with permeabilities relative to K(+) being P(Cs)+/P(K)+(1.06) approximately P(Na)+/P(K)+(1.04) approximately P(Rb)+/P(K)+(1.02) approximately P(Li)+/P(K)+(0.96), and was essentially impermeable to Ca(2+) and Mg(2+) (P(Ca)2+/P(K)+ approximately P(Mg)2+/P(K)+ < 0.001), with intracellular Mg(2+) (100 microm to 1 mm) causing inward rectification. Pore radius, estimated by fitting relative permeabilities of organic cations to the Renkin equation, was 0.41 nm. This channel exhibited significantly different properties compared with previously reported NC(Ca-ATP) channels, including different sensitivity to block by various adenine nucleotides (EC(50) of 0.79 microm for [ATP](i), with no block by AMP or ADP), and activation by submicromolar [Ca](i). The apparent dissociation constant for Ca(2+) was voltage dependent (0.12, 0.31, and 1.5 microm at -40, -80, and -120 mV, respectively), with a Hill coefficient of 1.5. Channel opening by [ATP](i) depletion was accompanied by and appeared to precede blebbing of the cell membrane, suggesting participation of this channel in cation flux involved in cell swelling. We conclude that NRAs from adult rat brain express a 35 pS NC(Ca-ATP) channel that may play an important role in the pathogenesis of brain swelling.
Our aim was to investigate the neuromodulatory role of diadenosine tetraphosphate (Ap(4)A). Ap(4)A-binding sites were detected in striatum and hippocampus membranes using [(35)S]-ADP beta S as radioligand and Ap(4)A and epsilon-(Ap(4)A), di-ethenoadenosine tetraphosphate, as displacers. Effects of epsilon-(Ap(4)A) on extracellular glutamate levels were studied using intracerebral perfusion. Both areas contain high-affinity binding sites for [(35)S]-ADP beta S with K(d) values in the low nM range. [(35)S]-ADP beta S binding was displaced by Ap(4)A and epsilon-(Ap(4)A). At 1 and 10 microM doses, epsilon-(Ap(4)A) markedly decreased glutamate levels in the striatum. The possibility of Ap(4)A acting as an endogenous modulator of excitatory neurotransmission is discussed.