ABSTRACT
[ ABSTRACT] AIM:To investigate the genetic cause of 2 Chinese families with Marfan syndrome .METHODS:The clinical and laboratory investigations were performed in the 2 unrelated Chinese families .Family 1 had 1 patient with cardiac problem.Family 2 had 2 patients:one died, and the other with respiratory and cardiac problems .Next generation sequencing and Sanger sequencing in the Marfan syndrome causal gene FBN1 were performed in the patient , his unaffected sister and the parents of family 1.Sanger sequencing covering all the exons and intron-exon boundaries were performed in the patient and the parents in family 2.Bioinformatic analysis was engaged in the variations unravelled .Fifty healthy indi-viduals were also investigated in the same manner .RESULTS:Both patients were diagnosed with Marfan syndrome .A no-vel mutation c.4685G>A (p.Cys1562Tyr) was detected in the patient of family 1 but was absent in his parents and the unaffected sister .This is a previously unreported novel mutation .In the mutation a conserved Cys was substituted by a Tyr in amino acid 1562 affecting a TGF-βbinding domain and the secondary structure in the encoded protein .We also detected the mutation c.3706T>C (p.Cys1236Arg) in the patient of family 2.It was absent in the unaffected parents , and there-fore was a de novo mutation too.This mutation has been previously reported and known to be associated with neonatal Marfan syndrome .Both mutations were absent in the 50 healthy controls .We also compared the genotype and phenotypes of the 2 families.CONCLUSION:We report 2 de novo mutations in 2 Chinese families with Marfan syndrome .One of the 2 mutations is novel.The phenotype of the mutation c.4685G>A(p.Cys1562Tyr) in family 1 is associated with classical Marfan syndrome, while that of c.3706T>C (p.Cys1236Arg) in family 2 is with neonatal type of Marfan syndrome .De novo mutations may be a cause for a proportion of mutations underlying the disease .The novel mutation also expends the mutational spectrum of the FBN1 gene.
ABSTRACT
Objective To explore the effects of pyrrolidine dithiocarbamate (PDTC) on the acute lung injury and the activation of Nrf2 pathway after Paraquat (PQ) induced lung injury.Methods Fortyeight adult male SD rats with lung injury induced by PQ were randomly (random number) divided into control group and PDTC group.Three animals were sacrificed at every 1-week interval,7d,14d and 21 days after PQ intoxication,and the lungs of rats were removed for acute lung injury score after HE staining,and for lung fibrosis assessment after Masson staining,and the levels of reduced glutathione (GSH) and malondialdehyde (MDA) in the lung tissue homogenate were assayed and the phosphorylation of Nrf2 (nuclear-E2-related factor 2) was detected by Weston blot.The mean values of detected variables between two groups were compared by t test,and survival curve was tested by Wilcoxon (Gehan) test.Results The intoxication symptoms of rats were obvious,and 4 rats in control group and 9 rats in PDTC group survived until 21days.The survival time of animals in PDTC group was longer than that in control group (Wilcoxon (Gehan) =10.17023,P =0.001).The levels of MDA in control group were higher than those in PDTC group,while the levels of GSH in control group were lower than those in PDTC group.The levels of phosphorylation of Nrf2 in PDTC group were higher than those in control group at 1-week intervals,1-week:(0.32±0.04) vs.(0.23±0.05),P=0.003; 2-week:(0.62±0.06) vs.(0.33±0.03),P＜0.001; 3-week:(0.61 ±0.04) vs.(0.33±0.05),P＜0.001.The acute lung injury (ALI) scores in PDTC group were lower than those in control group,1-week:(5 ± 0.95) vs.(8 ± 1.23),P =0.002 ; 2-week:(9±1.18) vs.(11±1.02),P=0.019; 3-week:(11±1.33) vs.(12±1.42),P=0.002.The percentages of lung fibrosis at 1-week intervals after PQ intoxication were (40.87 ± 7.25) ％,(43.38 ±5.71)％ and (45.91 ± 3.97)％ in control group,and they were higher than those in PDTC group (32.92±2.34)％,(33.45 ±3.04)％ and (35.27 ±3.81)％ in PDTC group,P=0.017,0.001 and 0.001 respectively.Conclusions Attenuation of acute lung injury and lung fibrosis,and prolongation of survival time of SD rats by PDTC were associated with activation of Nrf2 pathway.