Interstitial lung and liver disease(ILLD) is caused by biallelic mutations in the methionyl-tRNA synthetase(MARS) gene. To date, no genetic changes other than missense variants were reported in the literature. Here, w...Interstitial lung and liver disease(ILLD) is caused by biallelic mutations in the methionyl-tRNA synthetase(MARS) gene. To date, no genetic changes other than missense variants were reported in the literature. Here, we report a five-month old female infant with typical ILLD(failure to thrive, developmental delay, jaundice, diffuse interstitial lung disease, hepatomegaly with severe steatosis, anemia, and thrombocytosis) showing novel phenotypes such as kidney stones, acetabular dysplasia, prolonged fever, and extreme leukocytosis. Whole exome sequencing revealed a novel truncating variant(c.2158 C>T/p.Gln720 Stop) together with a novel tri-nucleotide insertion(c.893_894 insTCG that caused the insertion of an arginine at amino acid position 299) in the MARS gene.展开更多
Background:The aberrant intraellular expression of a mitochondrial aspartyl tRNA synthetase 2(DARS2)has been reported in human cancers.Nevertheless its critical role and detailed mechanism in lung adenocarcinoma(LUAD)...Background:The aberrant intraellular expression of a mitochondrial aspartyl tRNA synthetase 2(DARS2)has been reported in human cancers.Nevertheless its critical role and detailed mechanism in lung adenocarcinoma(LUAD)remain unexplored.Methods:Initially,The Cancer Genome Atlas(TCGA)based Gene Expression Profiling Interactive Analysis(GEPIA)database (http:/gepia.cancer-pku.cn/)was used to analyze the prognostic relevance of DARS2 expression in LUAD.Further,cell counting kit(CCK)8,immunostaining,and transwell invasion assays in LUAD cell lines in vitro,as well as DARS2 silence on LUAD by tumorigenicity experiments in wivo in nude mice,were performed.Besides,we analyzed the expression levels of p-PI3K(phosphorylated Phosphotylinosital3 kinase),PI3K,AKT(Protein Kinase B),p-AKT(phosphorylated Protein Kinase B),PCNA(proliferating cell nudear antigen),cleaved-caspase 3,E cadherin,and N-cadherin proteins using the Westem blot analysis.Results:LUAD tissues showed higher DARS2 expression compared to normal tissues.Upregulation of DARS2 could be related to Tumor-Node-Metastasis(TNM)stage,high lymph node metastasis,and inferior prognosis.DARS2 silence decreased the proliferation,migration,and invasion abilities of LUAD cells.In addition,the DARS2 downregulation decreased the PCNA and N-cadherin expression and increased cleaved:caspase 3 and E cadherin expressions in LUAD cells,coupled with the inactivation of the PI3K/AKT signaling pathway.Moreover,DARS2 silence impaired the tumonigenicity of LUAD in vivo.Interestingly,let:7b-5p could recognize DARS2 through a complementary sequence.Mechanistically,the increased let 7b 5p expression attenuated the promo oncogenic action of DARS2 during LUAD progression,which were inversely correlated to each other in the LUAD tssues Conclusion:In summary,let 7b-5p,downregulated DARS2 expression,regulating the progression of LUAD cells by the PI3K/AKT signaling pathway.展开更多
Abstract The details of species- spe- cific aminoacylation in Oryza sativa mitochondrial tRNATrp by bacterial and eukaryotic (cytoplasm) tryptophanyl-tRNA synthetases (TrpRS) were inves- tigated. Seven single or multi...Abstract The details of species- spe- cific aminoacylation in Oryza sativa mitochondrial tRNATrp by bacterial and eukaryotic (cytoplasm) tryptophanyl-tRNA synthetases (TrpRS) were inves- tigated. Seven single or multiple mutations of three bases (G73, U72, A 68) were made in O. sativa mi- tochondrial tRNATrp to the corresponding nucleotides present in human tRNATrp. In vitro transcripts of these mutant genes were tryptophanylated by Bacil- lus subtilis and human tryptophanyl-tRNA syntheta- ses (TrpRS), and the kinetic parameters were deter- mined. The results showed that the aminoacylation of seven mutant transcripts by B. subtilis TrpRS was 53.33%―99.79% less efficient than that by wild-type O. sativa mitochondrial tRNATrp, but was 4―330 times more efficient than that by human TrpRS. The mutant MPH7 (G73, U72 and C68 in O. sativa mito- chondrial tRNA were all replaced by the counterpart residues from human tRNATrp and showed a great change in aminoacylation efficiency. Our results in- dicate that the species-specific identity elements of O. sativa mitochondrial tRNATrp are similar to bacterial and eukaryotic (cytoplasm). They are mainly located at the discriminator base, the first and the fifth pairs of bases, the discriminator base G73, two bases in the acceptor stem G1/U72 and U5/A68. Our results also provide new data in support of the hypothesis that mitochondrial tRNATrp is of eubacterial origin.展开更多
BACKGROUND The mitochondrial respiratory chain defects have become the most common cause of neurometabolic disorders in children and adults,which can occur at any time in life,often associated with neurological dysfun...BACKGROUND The mitochondrial respiratory chain defects have become the most common cause of neurometabolic disorders in children and adults,which can occur at any time in life,often associated with neurological dysfunction,and lead to chronic disability and premature death.Approximately one-third of patients with mitochondrial disease have biochemical defects involving multiple respiratory chain complexes,suggesting defects in protein synthesis within the mitochondria.We here report a child with VARS2 gene mutations causing mitochondrial disease.CASE SUMMARY A girl,aged 3 years and 4 mo,had been unable to sit and crawl alone since birth,with obvious seizures and microcephaly.Brain magnetic resonance imaging showed symmetrical,flaky,long T1-weighted and low T2-weighted signals in the posterior part of the bilateral putamen with a high signal shadow.T2 fluidattenuated inversion recovery imaging showed a slightly high signal and diffusion-weighted imaging showed an obvious high signal.Whole-exome gene sequencing revealed a compound heterozygous mutation in the VARS2 gene,c.1163(exon11)C>T and c.1940(exon20)C>T,which was derived from the parents.The child was diagnosed with combined oxidative phosphorylation deficiency type 20.CONCLUSION In this patient,mitochondrial disorders including Leigh syndrome and MELAS syndrome(mitochondrial myopathy,encephalopathy,lactic acidosis,and stroke-like episodes)were ruled out,and combined oxidative phosphorylation deficiency type 20 was diagnosed,expanding the phenotypic spectrum of the disease.展开更多
基金Supported by the National Natural Science Foundation of China,No.81570468
文摘Interstitial lung and liver disease(ILLD) is caused by biallelic mutations in the methionyl-tRNA synthetase(MARS) gene. To date, no genetic changes other than missense variants were reported in the literature. Here, we report a five-month old female infant with typical ILLD(failure to thrive, developmental delay, jaundice, diffuse interstitial lung disease, hepatomegaly with severe steatosis, anemia, and thrombocytosis) showing novel phenotypes such as kidney stones, acetabular dysplasia, prolonged fever, and extreme leukocytosis. Whole exome sequencing revealed a novel truncating variant(c.2158 C>T/p.Gln720 Stop) together with a novel tri-nucleotide insertion(c.893_894 insTCG that caused the insertion of an arginine at amino acid position 299) in the MARS gene.
文摘Background:The aberrant intraellular expression of a mitochondrial aspartyl tRNA synthetase 2(DARS2)has been reported in human cancers.Nevertheless its critical role and detailed mechanism in lung adenocarcinoma(LUAD)remain unexplored.Methods:Initially,The Cancer Genome Atlas(TCGA)based Gene Expression Profiling Interactive Analysis(GEPIA)database (http:/gepia.cancer-pku.cn/)was used to analyze the prognostic relevance of DARS2 expression in LUAD.Further,cell counting kit(CCK)8,immunostaining,and transwell invasion assays in LUAD cell lines in vitro,as well as DARS2 silence on LUAD by tumorigenicity experiments in wivo in nude mice,were performed.Besides,we analyzed the expression levels of p-PI3K(phosphorylated Phosphotylinosital3 kinase),PI3K,AKT(Protein Kinase B),p-AKT(phosphorylated Protein Kinase B),PCNA(proliferating cell nudear antigen),cleaved-caspase 3,E cadherin,and N-cadherin proteins using the Westem blot analysis.Results:LUAD tissues showed higher DARS2 expression compared to normal tissues.Upregulation of DARS2 could be related to Tumor-Node-Metastasis(TNM)stage,high lymph node metastasis,and inferior prognosis.DARS2 silence decreased the proliferation,migration,and invasion abilities of LUAD cells.In addition,the DARS2 downregulation decreased the PCNA and N-cadherin expression and increased cleaved:caspase 3 and E cadherin expressions in LUAD cells,coupled with the inactivation of the PI3K/AKT signaling pathway.Moreover,DARS2 silence impaired the tumonigenicity of LUAD in vivo.Interestingly,let:7b-5p could recognize DARS2 through a complementary sequence.Mechanistically,the increased let 7b 5p expression attenuated the promo oncogenic action of DARS2 during LUAD progression,which were inversely correlated to each other in the LUAD tssues Conclusion:In summary,let 7b-5p,downregulated DARS2 expression,regulating the progression of LUAD cells by the PI3K/AKT signaling pathway.
基金supported by the Natural Science Foundation of Zhejiang Province(Grant No.302103).
文摘Abstract The details of species- spe- cific aminoacylation in Oryza sativa mitochondrial tRNATrp by bacterial and eukaryotic (cytoplasm) tryptophanyl-tRNA synthetases (TrpRS) were inves- tigated. Seven single or multiple mutations of three bases (G73, U72, A 68) were made in O. sativa mi- tochondrial tRNATrp to the corresponding nucleotides present in human tRNATrp. In vitro transcripts of these mutant genes were tryptophanylated by Bacil- lus subtilis and human tryptophanyl-tRNA syntheta- ses (TrpRS), and the kinetic parameters were deter- mined. The results showed that the aminoacylation of seven mutant transcripts by B. subtilis TrpRS was 53.33%―99.79% less efficient than that by wild-type O. sativa mitochondrial tRNATrp, but was 4―330 times more efficient than that by human TrpRS. The mutant MPH7 (G73, U72 and C68 in O. sativa mito- chondrial tRNA were all replaced by the counterpart residues from human tRNATrp and showed a great change in aminoacylation efficiency. Our results in- dicate that the species-specific identity elements of O. sativa mitochondrial tRNATrp are similar to bacterial and eukaryotic (cytoplasm). They are mainly located at the discriminator base, the first and the fifth pairs of bases, the discriminator base G73, two bases in the acceptor stem G1/U72 and U5/A68. Our results also provide new data in support of the hypothesis that mitochondrial tRNATrp is of eubacterial origin.
文摘BACKGROUND The mitochondrial respiratory chain defects have become the most common cause of neurometabolic disorders in children and adults,which can occur at any time in life,often associated with neurological dysfunction,and lead to chronic disability and premature death.Approximately one-third of patients with mitochondrial disease have biochemical defects involving multiple respiratory chain complexes,suggesting defects in protein synthesis within the mitochondria.We here report a child with VARS2 gene mutations causing mitochondrial disease.CASE SUMMARY A girl,aged 3 years and 4 mo,had been unable to sit and crawl alone since birth,with obvious seizures and microcephaly.Brain magnetic resonance imaging showed symmetrical,flaky,long T1-weighted and low T2-weighted signals in the posterior part of the bilateral putamen with a high signal shadow.T2 fluidattenuated inversion recovery imaging showed a slightly high signal and diffusion-weighted imaging showed an obvious high signal.Whole-exome gene sequencing revealed a compound heterozygous mutation in the VARS2 gene,c.1163(exon11)C>T and c.1940(exon20)C>T,which was derived from the parents.The child was diagnosed with combined oxidative phosphorylation deficiency type 20.CONCLUSION In this patient,mitochondrial disorders including Leigh syndrome and MELAS syndrome(mitochondrial myopathy,encephalopathy,lactic acidosis,and stroke-like episodes)were ruled out,and combined oxidative phosphorylation deficiency type 20 was diagnosed,expanding the phenotypic spectrum of the disease.
