Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (OMIM 208085) is an autosomal recessive disorder that is caused by mutations in 2 interacting genes VPS33B and VIPAS39. Mutations in VPS33B gene account...Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (OMIM 208085) is an autosomal recessive disorder that is caused by mutations in 2 interacting genes VPS33B and VIPAS39. Mutations in VPS33B gene account for most cases of ARC. As low or normal gamma-glutamyl transpeptidase (GGT) activity has been described in all patients with ARC syndrome identified so far, ARC syndrome is a possible diagnosis for low GGT cholestasis. Here we describe a Chinese patient with neonatal cholestasis and a high GGT level in three consecutive tests. She had other typical manifestations of ARC syndrome, including arthrogryposis multiplex congenita, renal involvement and ichthyosis. Genetic study of the VPS33B gene further confirmed the diagnosis by identification of compound heterozygosity of two known disease-causing mutations, c.403+2T > A and c.1509-1510insG. The mechanism of high GGT in this patient is unclear. Nevertheless, this case indicates that ARC syndrome cannot be excluded from the differential diagnosis of neonatal cholestasis even if high GGT activity is found.展开更多
Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome is a rare genetic disorder and has not been described in China. We present a female infant with neonatal intrahepatic cholestasis from a Chinese family ...Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome is a rare genetic disorder and has not been described in China. We present a female infant with neonatal intrahepatic cholestasis from a Chinese family with ARC syndrome. All 23 coding exons and flanking introns of the VPS33B gene were amplified and sequenced using peripheral lymphocyte genomic DNA of the patient and her parents. Genetic testing revealed two novel mutations (c.1033delA and c.1567C>T) in the VPS33B gene. The patient is a compound heterozygote and her parents were heterozygous for each of the mutations.展开更多
BACKGROUND The VPS33B(OMIM:608552)gene is located on chromosome 15q26.1.We found a female infant with autosomal recessive arthrogryposis,renal dysfunction and cholestasis syndrome 1(ARCS1)caused by mutation in VPS33B....BACKGROUND The VPS33B(OMIM:608552)gene is located on chromosome 15q26.1.We found a female infant with autosomal recessive arthrogryposis,renal dysfunction and cholestasis syndrome 1(ARCS1)caused by mutation in VPS33B.The child was diagnosed with ARCS1(OMIM:208085)after the whole exome sequencing revealed two heterozygous mutations(c.96+1G>C,c.242delT)in the VPS33B gene.CASE SUMMARY We report a Chinese female infant with neonatal cholestasis disorder,who was eventually diagnosed with ARCS1 by genetic analysis.Genetic testing revealed two new mutations(c.96+1G>C and c.242delT)in VPS33B,which is the causal gene.The patient was compound heterozygous,and her parents were both heterozygous.CONCLUSION This study extends the mutational spectrum of the VPS33B gene to provide a molecular basis for the etiological diagnosis of ARCS1 and for genetic counseling of the family.展开更多
The presence of VPS33B in tumors has rarely been reported.Downregulated VPS33B protein expression is an unfavorable factor that promotes the pathogenesis of lung adenocar-cinoma(LUAD).Overexpressed VPS33B was shown to...The presence of VPS33B in tumors has rarely been reported.Downregulated VPS33B protein expression is an unfavorable factor that promotes the pathogenesis of lung adenocar-cinoma(LUAD).Overexpressed VPS33B was shown to reduce the migration,invasion,metas-tasis,and chemoresistance of LUAD cells to cisplatin(DDP)in vivo and in vitro.Mechanistic analyses have indicated that VPS33B first suppresses epidermal growth factor receptor(EGFR)Ras/ERK signaling,which further reduces the expression of the oncogenic factor C-Myc.Down-regulated c-Myc expression reduces the rate at which it binds the p53 promoter and weakens its transcription inhibition;therefore,decreased C-Myc stimulates p53 expression,leading to decreased epithelial-to-mesenchymal transition(EMT)signal.NESG1 has been shown to be an unfavorable indicator of non-small-cell lung cancer(NSCLC).Here,NESG1 Was identified as an interactive protein of VPS33B.In addition,NESG1 was found to exhibit mutual stimulation with VPS33B via reduced RAS/ERK/c-Jun-mediated transcription repression.Knockdown of NESG1 activated EGFR/Ras/ERK/c-Myc signaling and further downregulated p53 expression,which thus activated EMT signaling and promoted LUAD migration and invasion.Finally,we observed that nicotine suppressed VPS33B expression by inducing PI3K/AKT/c-Jun-mediated transcription suppression.Our study demonstrates that VPS33B as a tumor suppressor is signif-icantly involved in the pathogenesis of LUAD.展开更多
基金Supported by National Natural Science Foundation of China,No.81070281
文摘Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (OMIM 208085) is an autosomal recessive disorder that is caused by mutations in 2 interacting genes VPS33B and VIPAS39. Mutations in VPS33B gene account for most cases of ARC. As low or normal gamma-glutamyl transpeptidase (GGT) activity has been described in all patients with ARC syndrome identified so far, ARC syndrome is a possible diagnosis for low GGT cholestasis. Here we describe a Chinese patient with neonatal cholestasis and a high GGT level in three consecutive tests. She had other typical manifestations of ARC syndrome, including arthrogryposis multiplex congenita, renal involvement and ichthyosis. Genetic study of the VPS33B gene further confirmed the diagnosis by identification of compound heterozygosity of two known disease-causing mutations, c.403+2T > A and c.1509-1510insG. The mechanism of high GGT in this patient is unclear. Nevertheless, this case indicates that ARC syndrome cannot be excluded from the differential diagnosis of neonatal cholestasis even if high GGT activity is found.
基金Supported by National Natural Science Foundation of China,No.81070281
文摘Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome is a rare genetic disorder and has not been described in China. We present a female infant with neonatal intrahepatic cholestasis from a Chinese family with ARC syndrome. All 23 coding exons and flanking introns of the VPS33B gene were amplified and sequenced using peripheral lymphocyte genomic DNA of the patient and her parents. Genetic testing revealed two novel mutations (c.1033delA and c.1567C>T) in the VPS33B gene. The patient is a compound heterozygote and her parents were heterozygous for each of the mutations.
基金Supported by the Hainan Province Clinical Medical Center,No.(2021)75 and(2021)276。
文摘BACKGROUND The VPS33B(OMIM:608552)gene is located on chromosome 15q26.1.We found a female infant with autosomal recessive arthrogryposis,renal dysfunction and cholestasis syndrome 1(ARCS1)caused by mutation in VPS33B.The child was diagnosed with ARCS1(OMIM:208085)after the whole exome sequencing revealed two heterozygous mutations(c.96+1G>C,c.242delT)in the VPS33B gene.CASE SUMMARY We report a Chinese female infant with neonatal cholestasis disorder,who was eventually diagnosed with ARCS1 by genetic analysis.Genetic testing revealed two new mutations(c.96+1G>C and c.242delT)in VPS33B,which is the causal gene.The patient was compound heterozygous,and her parents were both heterozygous.CONCLUSION This study extends the mutational spectrum of the VPS33B gene to provide a molecular basis for the etiological diagnosis of ARCS1 and for genetic counseling of the family.
基金supported by national nature science fund of China(grant number81572247)Nature science fund of Guangdong Province(grant numbers 2017A030313702,2015A030311005)+2 种基金Shenzhen health system science foundation(grant number SZBC2018019)the Supporting plan for Special Talents in Guangdong Province(grant number 2016TQ03R466)Guangzhou science and technology plan(grant number 201804010023)。
文摘The presence of VPS33B in tumors has rarely been reported.Downregulated VPS33B protein expression is an unfavorable factor that promotes the pathogenesis of lung adenocar-cinoma(LUAD).Overexpressed VPS33B was shown to reduce the migration,invasion,metas-tasis,and chemoresistance of LUAD cells to cisplatin(DDP)in vivo and in vitro.Mechanistic analyses have indicated that VPS33B first suppresses epidermal growth factor receptor(EGFR)Ras/ERK signaling,which further reduces the expression of the oncogenic factor C-Myc.Down-regulated c-Myc expression reduces the rate at which it binds the p53 promoter and weakens its transcription inhibition;therefore,decreased C-Myc stimulates p53 expression,leading to decreased epithelial-to-mesenchymal transition(EMT)signal.NESG1 has been shown to be an unfavorable indicator of non-small-cell lung cancer(NSCLC).Here,NESG1 Was identified as an interactive protein of VPS33B.In addition,NESG1 was found to exhibit mutual stimulation with VPS33B via reduced RAS/ERK/c-Jun-mediated transcription repression.Knockdown of NESG1 activated EGFR/Ras/ERK/c-Myc signaling and further downregulated p53 expression,which thus activated EMT signaling and promoted LUAD migration and invasion.Finally,we observed that nicotine suppressed VPS33B expression by inducing PI3K/AKT/c-Jun-mediated transcription suppression.Our study demonstrates that VPS33B as a tumor suppressor is signif-icantly involved in the pathogenesis of LUAD.
