1.Analysis of Coexisting Gene with NRAS in Acute Myeloid Leukemia.
Ye-Ping SHENG ; Hai-Ying HUA ; Hong-Ying CHAO ; Wen-Yan ZHU ; Zhi-Qing WANG ; Yan ZHANG ; Ye ZHOU
Journal of Experimental Hematology 2022;30(2):351-356
OBJECTIVE:
To investigate the coexisting mutations and clinical significance of Homo sapiens neuroblastoma RAS viral oncogene homolog (NRAS) gene in acute myeloid leukemia (AML) patients.
METHODS:
High-throughput DNA sequencing and Sanger sequencing were used to detect 51 gene mutations. The occurrence, clinical characteristics and treatment efficacy of coexisting genes with NRAS were investigated.
RESULTS:
A total of 57 NRAS mutations (17.5%) were detected in 326 patients with AML. Compared with the patients in NRAS non-mutation group, patients in the mutant group were younger (P=0.018) and showed lower platelet count (P=0.033), but there was no significant difference in peripheral leukocyte count, hemoglobin, and sex. For FAB classification, NRAS mutation and M2 subtype showed mutually exclusive (P=0.038). Among 57 patients carried with NRAS mutation, 51 (89.5%) patients carried with other gene mutations, 25 (43.9%) carried with double gene mutations, 10 (17.5%) carried with 3 gene mutations, and 16 (28.1%) corried with ≥ 4 gene mutations. The most common coexisting gene mutation was KRAS (24.6%, 14/57), followed by FLT3-ITD (14.0%, 8/57), RUNX1 (12.3%, 7/57), NPM1 (10.5%, 6/57), PTPN11 (10.5%, 6/57), DNMT3A (10.5%, 6/57) and so on. The age (P=0.013, P=0.005) and peripheral platelet count (P=0.007, P=0.021) of patients with NPM1 or DNMT3A mutations were higher than those of the patients with wild type, but there was no significant difference in peripheral leukocyte count and hemoglobin. Also, there was no significant difference in age, peripheral leukocyte count, hemoglobin, and peripheral platelet count between the patients in KRAS, FLT3-ITD, RUNX1 or PTPN11 mutant group and the wild group. Patients with FLT3-ITD mutations showed a lower complete remission (CR) rate (P=0.044). However, there was no significant difference in CR rate between the patients with KRAS, NPM1, RUNX1, PTPN11 or DNMT3A mutations and the wild group. The CR rate of the patents with single gene mutation, double gene mutations, 3 gene mutations, and≥ 4 gene mutations were decreased gradually, and there was no significant difference in CR rate between pairwise comparisons.
CONCLUSION
The mutation rate of NRAS mutation is 17.5%, 89.5% of AML patients with NRAS mutation coexist with additional gene mutations. The type of coexisting mutations has a certain impact on clinical characteristics and CR rate of patients with AML.
Core Binding Factor Alpha 2 Subunit/genetics*
;
GTP Phosphohydrolases/genetics*
;
Humans
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Leukemia, Myeloid, Acute/genetics*
;
Membrane Proteins/genetics*
;
Mutation
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Nucleophosmin
;
Prognosis
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Proto-Oncogene Proteins p21(ras)/genetics*
;
fms-Like Tyrosine Kinase 3
2.Role of Regulators of G-Protein Signaling 4 in Ca2+ Signaling in Mouse Pancreatic Acinar Cells.
Soonhong PARK ; Syng Ill LEE ; Dong Min SHIN
The Korean Journal of Physiology and Pharmacology 2011;15(6):383-388
Regulators of G-protein signaling (RGS) proteins are regulators of Ca2+ signaling that accelerate the GTPase activity of the G-protein alpha-subunit. RGS1, RGS2, RGS4, and RGS16 are expressed in the pancreas, and RGS2 regulates G-protein coupled receptor (GPCR)-induced Ca2+ oscillations. However, the role of RGS4 in Ca2+ signaling in pancreatic acinar cells is unknown. In this study, we investigated the mechanism of GPCR-induced Ca2+ signaling in pancreatic acinar cells derived from RGS4-/- mice. RGS4-/- acinar cells showed an enhanced stimulus intensity response to a muscarinic receptor agonist in pancreatic acinar cells. Moreover, deletion of RGS4 increased the frequency of Ca2+ oscillations. RGS4-/- cells also showed increased expression of sarco/endoplasmic reticulum Ca2+ ATPase type 2. However, there were no significant alterations, such as Ca2+ signaling in treated high dose of agonist and its related amylase secretion activity, in acinar cells from RGS4-/- mice. These results indicate that RGS4 protein regulates Ca2+ signaling in mouse pancreatic acinar cells.
Acinar Cells
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Amylases
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Animals
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Calcium-Transporting ATPases
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GTP Phosphohydrolases
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GTP-Binding Proteins
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Mice
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Pancreas
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Proteins
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Receptors, Muscarinic
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Reticulum
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RGS Proteins
3.Involvement of Protein Kinase C Isoforms and Rho GTPase in Contractile Response of Swine Pulmonary Artery.
Bo Kyung KIM ; Jung Hwan KIM ; Seong Hyop KIM ; Min Jung KIM ; Yoon Soo KIM ; Jeong Ae LIM ; Yun Jung CHOI ; Nam Sick WOO ; Ye Chul LEE ; Sung Il CHO
Korean Journal of Anesthesiology 2001;40(2):229-237
BACKGROUND: It is well established that vascular contraction is caused by not only an increase in cytosolic Ca2+ level but also activations of Ca2+-sensitizing mechanisms including protein kinase C (PKC) and low molecular GTP binding protein. However, the roles of PKC and RhoA, a low molecular GTP-binding protein, on the receptor agonist-mediated contraction in swine pulmonary artery has not been clarified. In the present study, we examined the contribution of PKC isoform and RhoA to the arterial stimulants-induced contraction in swine pulmonary artery. METHOD: The large (> 5 mm), medium (1-3 mm) and small (< 1 mm in outer diameter) sized pulmonary arteries were excised and the contractions were recorded isometrically. The contents and subcellular distribution of PKC isoforms and RhoA were detected using immunoblotting. RESULTS: In medium pulmonary artery, norepinephrine (NE, 10 nM-30micrometer) led contraction in a dose-dependent manner. In large and small pulmonary arteries, however, NE failed to induce a contraction. Adding of 12-deoxyphorbol 13-isobutyrate (DPB, 1micrometer), a PKC activator, developed muscle force in 1 mM EGTA-contained Ca2+-free physiological salt solution. The expressions of PKC alpha, elsilon were significantly increased in medium pulmonary artery. NE (10micrometer) evoked the translocation of RhoA from cytosol to the membrane but not those of PKC isoforms. In Ca2+-free physiological salt solution, DPB (1micrometer) caused a translocation of PKC isoforms. CONCLUSIONS: These results support that NE induces contraction via RhoA pathway but not PKC pathway in swine pulmonary artery.
Cytosol
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GTP Phosphohydrolases*
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GTP-Binding Proteins
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Immunoblotting
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Membranes
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Norepinephrine
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Protein Isoforms
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Protein Kinase C*
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Protein Kinases*
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Pulmonary Artery*
;
Swine*
4.Epigenetic disruption of cell signaling in nasopharyngeal carcinoma.
Li-Li LI ; Xing-Sheng SHU ; Zhao-Hui WANG ; Ya CAO ; Qian TAO
Chinese Journal of Cancer 2011;30(4):231-239
Nasopharyngeal carcinoma (NPC) is a malignancy with remarkable ethnic and geographic distribution in southern China and Southeast Asia. Alternative to genetic changes, aberrant epigenetic events disrupt multiple genes involved in cell signaling pathways through DNA methylation of promoter CpG islands and/or histone modifications. These epigenetic alterations grant cell growth advantage and contribute to the initiation and progression of NPC. In this review, we summarize the epigenetic deregulation of cell signaling in NPC tumorigenesis and highlight the importance of identifying epigenetic cell signaling regulators in NPC research. Developing pharmacologic strategies to reverse the epigenetic-silencing of cell signaling regulators might thus be useful to NPC prevention and therapy.
Adaptor Proteins, Signal Transducing
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genetics
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metabolism
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Apoptosis
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genetics
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Carcinoma
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Cell Cycle
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genetics
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CpG Islands
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genetics
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DNA Damage
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genetics
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DNA Methylation
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Epigenesis, Genetic
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GTP Phosphohydrolases
;
genetics
;
metabolism
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Gene Silencing
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Humans
;
Nasopharyngeal Neoplasms
;
genetics
;
metabolism
;
pathology
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Repressor Proteins
;
genetics
;
metabolism
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Signal Transduction
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Tumor Suppressor Protein p53
;
genetics
;
metabolism
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beta Catenin
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genetics
;
metabolism
;
ras Proteins
;
genetics
;
metabolism
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rho GTP-Binding Proteins
;
genetics
;
metabolism
5.Small GTPases and formins in mammalian oocyte maturation: cytoskeletal organizers.
Clinical and Experimental Reproductive Medicine 2011;38(1):1-5
The maturation process of mammalian oocytes accompanies an extensive rearrangement of the cytoskeleton and associated proteins. As this process requires a delicate interplay between the cytoskeleton and its regulators, it is often targeted by various external and internal adversaries that affect the congression and/or segregation of chromosomes. Asymmetric cell division in oocytes also requires specific regulators of the cytoskeleton, including formin-2 and small GTPases. Recent literature providing clues regarding how actin filaments and microtubules interact during spindle migration in mouse oocytes are highlighted in this review.
Actin Cytoskeleton
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Animals
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Asymmetric Cell Division
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Cytoskeleton
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GTP Phosphohydrolases
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Humans
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Mice
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Microtubules
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Monomeric GTP-Binding Proteins
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Nerve Tissue Proteins
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Oocytes
;
Proteins
6.Comparison of human and Drosophila atlastin GTPases.
Fuyun WU ; Xiaoyu HU ; Xin BIAN ; Xinqi LIU ; Junjie HU
Protein & Cell 2015;6(2):139-146
Formation of the endoplasmic reticulum (ER) network requires homotypic membrane fusion, which involves a class of atlastin (ATL) GTPases. Purified Drosophila ATL is capable of mediating vesicle fusion in vitro, but such activity has not been reported for any other ATLs. Here, we determined the preliminary crystal structure of the cytosolic segment of Drosophila ATL in a GDP-bound state. The structure reveals a GTPase domain dimer with the subsequent three-helix bundles associating with their own GTPase domains and pointing in opposite directions. This conformation is similar to that of human ATL1, to which GDP and high concentrations of inorganic phosphate, but not GDP only, were included. Drosophila ATL restored ER morphology defects in mammalian cells lacking ATLs, and measurements of nucleotide-dependent dimerization and GTPase activity were comparable for Drosophila ATL and human ATL1. However, purified and reconstituted human ATL1 exhibited no in vitro fusion activity. When the cytosolic segment of human ATL1 was connected to the transmembrane (TM) region and C-terminal tail (CT) of Drosophila ATL, the chimera still exhibited no fusion activity, though its GTPase activity was normal. These results suggest that GDP-bound ATLs may adopt multiple conformations and the in vitro fusion activity of ATL cannot be achieved by a simple collection of functional domains.
Animals
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Dimerization
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Drosophila
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Drosophila Proteins
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chemistry
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genetics
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Endoplasmic Reticulum
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chemistry
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GTP Phosphohydrolases
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chemistry
;
genetics
;
GTP-Binding Proteins
;
chemistry
;
genetics
;
Guanosine Diphosphate
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chemistry
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metabolism
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Humans
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Membrane Proteins
;
chemistry
;
genetics
;
Mutation
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Protein Conformation
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Protein Structure, Secondary
7.Mechanism underlying the anterograde transport of the influenza A virus transmembrane proteins and genome in host cytoplasm.
Xiaojuan CHI ; Song WANG ; Yifan HUANG ; Jilong CHEN
Chinese Journal of Biotechnology 2012;28(9):1021-1030
Influenza virus assembly requires the completion of viral protein and vRNP transport to the assembly site at the plasma membrane. Therefore, efficient regulation of intracellular transport of the viral proteins and vRNPs to the surface of the host cell is especially important for virus morphogenesis. Influenza A virus uses the machineries of host cells to transport its own components including ribonucleoproteins (vRNPs) and three transmembrane proteins hemagglutinin (HA), neuraminidase (NA) and matrix 2 protein (M2). It has been shown that newly synthesized vRNPs are associated with active form of Rab11 and accumulate at recycling endosomes adjacent to the microtubule organizing center (MTOC) following nuclear export. Subsequently, they are transported along the microtubule network toward the plasma membranes in cargo vesicles. The viral transmembrane proteins are translated on the rough endoplasmic reticulum and transported to the virus assembly site at the plasma membrane. It has been found that several host factors such as ARHGAP21 and GTPase Cdc42 are involved in regulation of intracellular trafficking of influenza A virus transmembrane proteins including NA. In this review, we will highlight the current knowledge about anterograde transport and its regulation of the influenza A virus transmembrane proteins and genome in the host cytoplasm.
Cytoplasm
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metabolism
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GTP Phosphohydrolases
;
metabolism
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GTPase-Activating Proteins
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metabolism
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Genome, Viral
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Hemagglutinin Glycoproteins, Influenza Virus
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metabolism
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Humans
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Influenza A virus
;
genetics
;
pathogenicity
;
physiology
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Neuraminidase
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metabolism
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Protein Transport
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Ribonucleoproteins
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metabolism
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Viral Matrix Proteins
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metabolism
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cdc42 GTP-Binding Protein
;
metabolism
8.A SPG3A mutation with a novel foot phenotype of hereditary spastic paraplegia in a Chinese Han family.
Xun-hua LI ; Chun SONG ; Su-qin CHEN ; Yan ZHOU ; Hui GUO ; Chun-long ZHOU ; Zhi-yun YANG ; Yin-xing LIANG ; Yi-ming WANG
Chinese Medical Journal 2007;120(9):834-837
Adolescent
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Adult
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Aged
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Child
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Child, Preschool
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China
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ethnology
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Evoked Potentials, Somatosensory
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Evolution, Molecular
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Female
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Foot Deformities, Congenital
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genetics
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GTP Phosphohydrolases
;
genetics
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GTP-Binding Proteins
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Genes, Dominant
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Humans
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Male
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Membrane Proteins
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Middle Aged
;
Mutation
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Spastic Paraplegia, Hereditary
;
genetics
9.SPG3A-hereditary spastin paraplegia with genetic anticipation and incomplete penetrance.
Chinese Journal of Medical Genetics 2007;24(1):15-18
OBJECTIVETo analyze the SPG3A coding sequence and clinical features in a family with dominantly inherited hereditary spastin paraplegia (HSP) characterized by incomplete genetic penetrance and genetic anticipation.
METHODSAnalysis of the SPG3A coding sequence, being sequence variations in SPG4/spastin (S44L and P45Q) and SPG6/nipa1([GCG]5-11) genes were performed for the proband, his affected son, his unaffected parents and unaffected brother. One hundred normal individuals were selected as controls.
RESULTSSPG3A mutation V253I in the proband, his affected son, and unexpectedly, in his asymptomatic, 72 year old father was identified. No mutation at the same site was found in the other members of this family as well as the control.
CONCLUSIONIncomplete genetic penetrance due to SPG3A mutation V253I was observed in this family. This is the second report. Marked phenotype variation (genetic non-penetrance, adult versus childhood onset symptoms) between subjects with the same SPG3A mutation indicates the influence of modifying genetic or environmental factors. Progressively earlier symptom onset and increasing symptom severity in this family is consistent with genetic anticipation which has not been previously reported in SPG3A-HSP.
Aged ; Aged, 80 and over ; Anticipation, Genetic ; Base Sequence ; DNA Mutational Analysis ; Female ; Follow-Up Studies ; GTP Phosphohydrolases ; genetics ; GTP-Binding Proteins ; Humans ; Male ; Membrane Proteins ; Middle Aged ; Pedigree ; Penetrance ; Polymerase Chain Reaction ; Spastic Paraplegia, Hereditary ; genetics
10.The role of the exocyst in renal ciliogenesis, cystogenesis, tubulogenesis, and development
Kidney Research and Clinical Practice 2019;38(3):260-266
The exocyst is a highly conserved eight-subunit protein complex (EXOC1–8) involved in the targeting and docking of exocytic vesicles translocating from the trans-Golgi network to various sites in renal cells. EXOC5 is a central exocyst component because it connects EXOC6, bound to the vesicles exiting the trans-Golgi network via the small GTPase RAB8, to the rest of the exocyst complex at the plasma membrane. In the kidney, the exocyst complex is involved in primary ciliognesis, cystogenesis, and tubulogenesis. The exocyst, and its regulators, have also been found in urinary extracellular vesicles, and may be centrally involved in urocrine signaling and repair following acute kidney injury. The exocyst is centrally involved in the development of other organs, including the eye, ear, and heart. The exocyst is regulated by many different small GTPases of the RHO, RAL, RAB, and ARF families. The small GTPases, and their guanine nucleotide exchange factors and GTPase-activating proteins, likely give the exocyst specificity of function. The recent development of a floxed Exoc5 mouse line will aid researchers in studying the role of the exocyst in multiple cells and organ types by allowing for tissue-specific knockout, in conjunction with Cre-driver mouse lines.
Acute Kidney Injury
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Animals
;
Cell Membrane
;
Ear
;
Exocytosis
;
Extracellular Vesicles
;
GTP Phosphohydrolases
;
GTPase-Activating Proteins
;
Guanine Nucleotide Exchange Factors
;
Heart
;
Humans
;
Kidney
;
Mice
;
Monomeric GTP-Binding Proteins
;
Sensitivity and Specificity
;
trans-Golgi Network