title: Identification of novel mutations in the VPS33B gene involved in arthrogryposis, renal dysfunction, and cholestasis syndrome.
abstract: Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is an autosomal recessive disorder caused by mutations in the VPS33B and VIPAS39. Here, we report novel mutations identified in four patients with ARC syndrome. We analyzed the entire coding regions of the VPS33B and VIPAS39 genes by direct sequencing. To detect novel splice site mutations, mRNA transcripts were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and sequencing. All four patients had compound heterozygous variants in the VPS33B gene. One patient had a previously reported splice site variant with unknown significance, c.239+5G>A, and a novel nonsense mutation, c.621G>A. The other three patients had the c.403+2T>A mutation, and each of them carried one of the splice site variants, c.239+5G>A or c.499-11G>A. c.239+5G>A and c.499-11G>A created novel splice sites which resulted in abnormal transcripts. No significant VIPAS39 mutation was detected in all patients. In patients suspected with ARC syndrome, mutation analysis of the VPS33B gene should be employed as a primary diagnostic test before performing invasive testing procedures such as organ biopsies. Performing mRNA analysis can be useful in predicting the pathogenic phenotype when the mutation seems to affect a normal splicing mechanism.
authors.affiliation: Department of Laboratory Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Seo
authors.affiliation: Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.
authors.forename: S M
authors.initials: SM
authors.lastname: Hwang
authors.affiliation: Department of Pediatrics, Seoul National University Children's Hospital, Seoul, South Korea.
authors.forename: J M
authors.initials: JM
authors.lastname: Ko
authors.affiliation: Department of Pediatrics, Seoul National University Children's Hospital, Seoul, South Korea.
authors.forename: J S
authors.initials: JS
authors.lastname: Ko
authors.affiliation: Department of Laboratory Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Hyun
authors.affiliation: Department of Laboratory Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: S I
authors.initials: SI
authors.lastname: Cho
authors.affiliation: Department of Laboratory Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: H
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine, National Medical Center, Seoul, South Korea.
authors.forename: S Y
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: M-W
authors.initials: MW
authors.lastname: Seong
authors.affiliation: Department of Laboratory Medicine, Seoul National University Hospital, Seoul, South Korea.
authors.forename: S S
authors.initials: SS
authors.lastname: Park
mesh_terms: D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics*; D002779:Cholestasis / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics*; D051437:Renal Insufficiency / Q000175:diagnosis / Q000235:genetics*; D056910:Republic of Korea; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; C411584:VPS33B protein, human; D033921:Vesicular Transport Proteins
keywords: ARC syndrome; VPS33B; arthrogryposis, renal dysfunction and cholestasis syndrome