PubMed · 1124700
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J H Joist, J F Mustard. 1975. Heparin lysolecithin, and platelet function.. https://doi.org/10.1007/978-1-4684-0946-8_22
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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.
The yeast ADP/ATP carrier (AAC) is a mitochondrial protein that is targeted to the inner membrane via the TIM10 and TIM22 translocase complexes. AAC is devoid of a typical mitochondrial targeting signal and its targeting and insertion are thought to be guided by internal amino acid sequences. Here we show that AAC contains a cryptic matrix targeting signal that can target up to two thirds of the N-terminal part of the protein to the matrix. This event is coordinated by the TIM23 translocase and displays all the features of the matrix-targeting pathway. However, in the context of the whole protein, this signal is 'masked' and rendered non-functional as the polypeptide is targeted to the inner membrane via the TIM10 and TIM22 translocases. Our data suggest that after crossing the outer membrane the whole polypeptide chain of AAC is necessary to commit the precursor to the TIM22-mediated inner membrane insertion pathway.
Because cellular and extract data have suggested that N-acetylaspartate (NAA) reflects neuronal mitochondrial function, we evaluated the quantitative relationship between NAA, high-energy phosphates, and ADP levels in the hippocampus and occipital lobe of 15 healthy volunteers. The ADP levels are calculated using the creatine kinase equilibrium and quantified (31)P and total creatine measurements. Using high-field quantitative MR spectroscopic imaging, we find that NAA and ADP concentrations in the hippocampal body are 9.7 +/- 1.5mM and 35 +/- 8microM, respectively. In the occipital lobe, NAA and ADP are 11.9 +/- 1.9mM and 32 +/- 12microM, respectively. There is a statistically significant positive correlation between NAA and ADP, with R = +0.80, p < 2 x 10(-7)in the hippocampal body. In an adjacent hippocampal NAA voxel, the correlation between NAA and ADP had a R = +0.62, p < 3 x 10(-4), whereas, in the occipital lobe, R = +0.67, p < 5 x 10(-5). There was no significant relationship NAA and either ATP or phosphocreatine. This positive relationship of NAA with ADP suggests a directional process wherein energetics may modulate mitochondrial function.