Dear Editor,Psoriasis,a chronic inflammatory cutaneous condition,is characterized by the development of red plaques with silvery scales,significantly affecting patients'quality of life and mental health[1].This co...Dear Editor,Psoriasis,a chronic inflammatory cutaneous condition,is characterized by the development of red plaques with silvery scales,significantly affecting patients'quality of life and mental health[1].This condition is thought to affect approximately 2%of the Western population,with diagnosis peaking in early adulthood[2].Vitamin D,a fat-soluble vitamin,is essential for phospho-calcium metabolism,calcium homeostasis,and bone health.展开更多
Background Dubin-Johnson syndrome(DJS),a rare autosomal recessive liver condition,is caused by biallelic loss-of-function mutations of the ABCC2 gene.This study aimed to investigate genetic variations in the drug effl...Background Dubin-Johnson syndrome(DJS),a rare autosomal recessive liver condition,is caused by biallelic loss-of-function mutations of the ABCC2 gene.This study aimed to investigate genetic variations in the drug efflux transporter ABCC2(MRP2)gene in patients with DJS and to characterise the expression and mechanism of the ABCC2 gene variant.Methods Trio whole exome sequencing was performed in the family to identify the genetic causes.Bioinformatics analysis was performed to assess pathogenicity.In in vitro experiments,site-directed mutagenesis was used to introduce ABCC2 variants in constructs then expressed in HEK293T,HuH-7 and HepG2 cell lines.The expression of total and cell membrane MRP2 was quantified in cells expressing the wild-type or variant forms.Chloroquine and MG132 were used to evaluate the effects of p.R393W on lysosomal and/or proteasomal degradation.Results The twin probands carry DJS-associated variants c.1177C>T(rs777902199)in the ABCC2 gene inherited from the father and the c.3632T>C mutation in the other allele inherited from the mother.The ABCC2 variant,c.1177C>T,results in a p.R393W substitution in MRP2 that is highly conserved among vertebrates,drastically decreasing the expression of mutant protein by promoting proteasomal degradation.Another variant c.3632T>C results in a p.L1211P substitution in MRP2,decreasing the expression of membrane MRP2 but not changing the expression of total protein.Conclusion These results strongly suggest that the p.R393W variant affects the stability of the MRP2 protein and decreases its expression by ubiquitin-mediated proteasomal degradation,and the p.L1211P decreases the expression of membrane MRP2,indicating that these two variants,respectively,cause a loss-of-function of the MRP2 protein and membrane MRP2 ultimately leading to DJS development.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.82573974 and 82373475)to Z.Y.
文摘Dear Editor,Psoriasis,a chronic inflammatory cutaneous condition,is characterized by the development of red plaques with silvery scales,significantly affecting patients'quality of life and mental health[1].This condition is thought to affect approximately 2%of the Western population,with diagnosis peaking in early adulthood[2].Vitamin D,a fat-soluble vitamin,is essential for phospho-calcium metabolism,calcium homeostasis,and bone health.
基金supported by the National Natural Science Foundation of China(82171701)the Medical Science and Technology Project of Zhejiang Province(2022YK839)+1 种基金the Social Programs of Wenzhou Technology Bureau(2020Y0419,2023Y0329)the Zhejiang Medical Association(2020ZYC-B23).
文摘Background Dubin-Johnson syndrome(DJS),a rare autosomal recessive liver condition,is caused by biallelic loss-of-function mutations of the ABCC2 gene.This study aimed to investigate genetic variations in the drug efflux transporter ABCC2(MRP2)gene in patients with DJS and to characterise the expression and mechanism of the ABCC2 gene variant.Methods Trio whole exome sequencing was performed in the family to identify the genetic causes.Bioinformatics analysis was performed to assess pathogenicity.In in vitro experiments,site-directed mutagenesis was used to introduce ABCC2 variants in constructs then expressed in HEK293T,HuH-7 and HepG2 cell lines.The expression of total and cell membrane MRP2 was quantified in cells expressing the wild-type or variant forms.Chloroquine and MG132 were used to evaluate the effects of p.R393W on lysosomal and/or proteasomal degradation.Results The twin probands carry DJS-associated variants c.1177C>T(rs777902199)in the ABCC2 gene inherited from the father and the c.3632T>C mutation in the other allele inherited from the mother.The ABCC2 variant,c.1177C>T,results in a p.R393W substitution in MRP2 that is highly conserved among vertebrates,drastically decreasing the expression of mutant protein by promoting proteasomal degradation.Another variant c.3632T>C results in a p.L1211P substitution in MRP2,decreasing the expression of membrane MRP2 but not changing the expression of total protein.Conclusion These results strongly suggest that the p.R393W variant affects the stability of the MRP2 protein and decreases its expression by ubiquitin-mediated proteasomal degradation,and the p.L1211P decreases the expression of membrane MRP2,indicating that these two variants,respectively,cause a loss-of-function of the MRP2 protein and membrane MRP2 ultimately leading to DJS development.
