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《Genetics in medicine》2023,25(9):100893
PurposeDevelopmentally regulated Guanosine-5'-triphosphate-binding protein 1 (DRG1) is a highly conserved member of a class of GTPases implicated in translation. Although the expression of mammalian DRG1 is elevated in the central nervous system during development, and its function has been implicated in fundamental cellular processes, no pathogenic germline variants have yet been identified. Here, we characterize the clinical and biochemical consequences of DRG1 variants.MethodsWe collate clinical information of 4 individuals with germline DRG1 variants and use in silico, in vitro, and cell-based studies to study the pathogenicity of these alleles.ResultsWe identified private germline DRG1 variants, including 3 stop-gained p.Gly541, p.Arg1401, p.Lys2631, and a p.Asn248Phe missense variant. These alleles are recessively inherited in 4 affected individuals from 3 distinct families and cause a neurodevelopmental disorder with global developmental delay, primary microcephaly, short stature, and craniofacial anomalies. We show that these loss-of-function variants (1) severely disrupt DRG1 messenger RNA/protein stability in patient-derived fibroblasts, (2) impair its GTPase activity, and (3) compromise its binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation of mouse Drg1 resulted in preweaning lethality.ConclusionOur work defines a new Mendelian disorder of DRG1 deficiency. This study highlights DRG1’s importance for normal mammalian development and underscores the significance of translation factor GTPases in human physiology and homeostasis. 相似文献
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The lactogen receptor has been suggested to associate with one or more G proteins despite the absence of a 7-transmembrane
spanning sequence. These studies were designed to determine whether lactogens acutely increase GTP binding to or GTPase activity
in Nb2 cell membrane. Incubation of Nb2 cell membrane with either ovine PRL (10 ng/ml) or diluent for 0–1 h resulted in a
decrease in total35S-GTP binding to both with no difference in GTP binding between PRL- and diluent-treated membranes. There was also no change
in35S-GTP binding to Nb2 cell membrane incubated with increasing oPRL concentrations (0.001–100 ng/ml) for 60 min. α-32P-GTP photoaffinity labelling was used to evaluate changes in GTP binding to specific G proteins. Photoaffinity labelling
of α-32P-GTP to no G protein was changed after preincubation with oPRL (10 ng/ml) for 0–60 min or with oPRL (0.01–10 ng/ml) for 60
min. Finally, it was determined whether oPRL had any acute effect on GTPase activity, as determined by release of32Pi from γ-32P-GTP. When Nb2 cell membrane was preincubated for 0–60 min with oPRL (10 ng/ml) or a range of oPRL concentrations (0–10 ng/ml),
no change in GTPase activity was observed. However, when Nb2 cells were incubated with lactogen for 0–7 h, GTPase activity
in equal quantities of Nb2 cell membrane prepared from those cells increased over time. Increased GTPase activity (64.9–74.4%;P<0.03 compared to 0 h) was observed after 4–7 h incubation with lactogen.
In summary, addition of lactogen to Nb2 cell membrane did not acutely increase either GTP binding or GTPase activity. Yet
when Nb2 cells were incubated with lactogen for 4 h prior to preparation of membrane, GTPase activity was significantly increased.
This evidence, in addition to our previous results showing that 4 h incubation with lactogen increased G protein β subunit
concentration and pertussis toxin-stimulated ADP-ribosylation of Gi, support a role for delayed lactogen modulation of one
or more G proteins in the Nb2 cell, requiring at least 4 h for maximal effect. 相似文献
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Summary GTP is generally required for hormonal stimulation of adenylate cyclase. On the other hand, the presence of GTP is essential for hormone-induced inhibition of adenylate cyclase in cell-free preparations of human platelets and other cells. In order to differentiate the dual roles of GTP in hormonal stimulation and inhibition of adenylate cyclase, we have studied the effect of adrenaline on the platelet enzyme under conditions where guanine mucleotides caused marked stimulation. In the presence of GTP (1 M), which by itself had no or only a small stimulatory effect on adenylate cyclase, adrenaline inhibited the basal and prostaglandin E1-stimulated forms of the enzyme. In contrast, the stable GTP analogues, GMP-P(NH)P and GTP--S, which caused a time-dependent, persistent activation of the enzyme, reversed or prevented the inhibitory effect of adrenaline. Cholera toxin, which activates adenylate cyclase presumably by inhibition of a specific GTPase, increased cyclase activity in platelet membranes up to 4-fold, and GTP addition (0.1–30 M) augmented this activation about 2-fold. The -adrenergic component of adrenaline (0.1–100 M), in a concentration-dependent manner, prevented the GTP-induced increase in cholera toxin-stimulated activity. The inhibition was also observed in enzyme preparations that had been fully activated by pretreatment with cholera toxin. These data suggest that -adrenergic agonists may inhibit platelet adenylate cyclase through increased inactivation of the enzyme, possibly involving a stimulation of the GTPase connected to the adenylate cyclase system.Abbreviations GMP-P(NH)P
guanylyl 5-imidodiphosphate
- GTP--S
guanosine 5-(-thio)triphosphate
- GTPase
guanosine 5-triphosphatase
- Pi
inorganic phosphate.
Parts of the data were presented in preliminary form (Jakobs and Schultz, 1978) 相似文献
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Y. Jin H. Zhong J.R. Omnaas R.R. Neubig H.I. Mosberg 《Chemical biology & drug design》2004,63(2):141-146
Abstract: Regulators of G‐protein signaling (RGS) proteins form a multifunctional signaling family. A key role of RGS proteins is binding to the G‐protein Gα‐subunit and acting as GTPase‐activating proteins (GAPs), thereby rapidly terminating G protein‐coupled receptor (GPCR) signaling. Using the published RGS4–Giα1 X‐ray structure we have designed and synthesized a series of cyclic peptides, modeled on the Giα Switch I region, that inhibit RGS4 GAP activity. These compounds should prove useful for elucidating RGS‐mediated activity and serve as a starting point for the development of a novel class of therapeutic agent. 相似文献
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Genetic analysis of Chinese families reveals a novel truncation allele of the retinitis pigmentosa GTPase regulator gene
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Fang Hu Xiang-Yun Zeng Lin-Lin Liu Yao-Ling Luo Yi-Ping Jiang Hui Wang Jing Xie Cheng-Quan Hu Lin Gan Liang Huang 《国际眼科》2014,7(5):753-758
AIM: To make comprehensive molecular diagnosis for retinitis pigmentosa (RP) patients in a consanguineous Han Chinese family using next generation sequencing based Capture-NGS screen technology.
METHODS: A five-generation Han Chinese family diagnosed as non-syndromic X-linked recessive RP (XLRP) was recruited, including four affected males, four obligate female carriers and eleven unaffected family members. Capture-NGS was performed using a custom designed capture panel covers 163 known retinal disease genes including 47 RP genes, followed by the validation of detected mutation using Sanger sequencing in all recruited family members.
RESULTS: Capture-NGS in one affected 47-year-old male reveals a novel mutation, c.2417_2418insG:p.E806fs, in exon ORF15 of RP GTPase regulator (RPGR) gene results in a frameshift change that results in a premature stop codon and a truncated protein product. The mutation was further validated in three of four affected males and two of four female carriers but not in the other unaffected family members.
CONCLUSION: We have identified a novel mutation, c.2417_2418insG:p.E806fs, in a Han Chinese family with XLRP. Our findings expand the mutation spectrum of RPGR and the phenotypic spectrum of XLRP in Han Chinese families, and confirms Capture-NGS could be an effective and economic approach for the comprehensive molecular diagnosis of RP. 相似文献
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肿瘤的发生、发展是多因素、多步骤参与的复杂过程,其中Ras信号通路及其相关因子又扮演着关键角色.Ras基因及其相关通路的异常在多种人类肿瘤中均可检测到.Ras-GTPase激活蛋白(Ras-GAPs)可视为一种肿瘤抑制基因的产物,它能够激活GTP酶,使活化的Ras蛋白转为非活化状态,终止信号转导,从而抑制肿瘤的发生.本文总结了关于Ras-GAPs在肿瘤中作用的研究新进展. 相似文献
10.
Lyra Razanadrakoto Fran?oise Cormier Vanessa Laurienté Elisabetta Dondi Laura Gardano Shulamit Katzav Lionel Guittat Nadine Varin-Blank 《Oncotarget》2015,6(4):2524-2538
Vav family members function as remarkable scaffold proteins that exhibit both GDP/GTP exchange activity for Rho/Rac GTPases and numerous protein-protein interactions via three adaptor Src-homology domains. The exchange activity is under the unique regulation by phosphorylation of tyrosine residues hidden by intra-molecular interactions. Deletion of the autoinhibitory N-terminal region results in an oncogenic protein, onco-Vav, leading to a potent activation of Rac GTPases whereas the proto-oncogene barely leads to transformation. Substitution of conserved residues of the SH2-SH3 adaptor region in onco-Vav reverses oncogenicity. While a unique substitution D797N did not affect transformation induced by onco-Vav, we demonstrate that this single substitution leads to transformation in the Vav1 proto-oncogene highlighting the pivotal role of the adaptor region. Moreover, we identified the cell junction protein β-catenin as a new Vav1 interacting partner. We show that the oncogenicity of activated Vav1 proto-oncogene is associated with a non-degradative phosphorylation of β-catenin at residues important for its functions and its redistribution along the cell membrane in fibroblasts. In addition, a similar interaction is evidenced in epithelial lung cancer cells expressing ectopically Vav1. In these cells, Vav1 is also involved in the modulation of β-catenin phosphorylation. Altogether, our data highlight that only a single mutation in the proto-oncogene Vav1 enhances tumorigenicity. 相似文献