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.

ARC Syndrome-Linked Vps33B Protein Is Required for Inflammatory Endosomal Maturation and Signal Termination

“…Our study demonstrates that the cause of death for Vps33B flies is not the bacterial load itself but exaggerated anti-microbial responses to non-pathogenic microbes, similar to sepsis that contributes to death in ARC patients (Jang et al, 2009; Seo et al, 2014). Furthermore, such exaggerated TLR signaling can cause innate immune paralysis (Hotchkiss et al, 2013), where the innate immune system, following a robust response to the first infection, fails to respond to secondary infections, possibly resulting in enhanced susceptibility of ARC patients to pathogenic microbes.…”

“…Persistent infections and sepsis are recurring symptoms in ARC patients (Jang et al, 2009; Seo et al, 2014). Our findings indicate that, rather than being an indirect consequence of failures in other organ systems, these complications could reflect direct roles of the ARC protein Vps33B in innate immunity.…”

“…Consistent with these observations, the mycobacterial virulence factor PtpA targets Vps33B for dephosphorylation, which contributes to intracellular persistence of Mycobacterium (Bach et al, 2008). Mutations in human Vps33B and VIPAS39 are responsible for arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome (Cullinane et al, 2010; Gissen et al, 2004), a fatal recessive disorder characterized by trafficking defects in multiple organ systems (Gissen et al, 2006; Tornieri et al, 2013) and persistent infections and sepsis (Jang et al, 2009; Seo et al, 2014). …”

VPS33B negatively modulated by nicotine functions as a tumor suppressor in colorectal cancer

“…Vacuolar protein sorting 33B (VPS33B) is a late endosome‐ and lysosome‐associated protein in the Sec‐1 domain family, and it plays an important role in the segregation of intracellular molecules into distinct organelles. Mutation of VPS33B is linked with arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, which is a rare autosomal recessive disease involving multiple systemic disorders . VPS33B is required for megakaryocyte biogenesis, platelet activation and in vivo thrombosis and homeostasis .…”

“…Mutation of VPS33B is linked with arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, which is a rare autosomal recessive disease involving multiple systemic disorders. 2,3 VPS33B is required for megakaryocyte biogenesis, platelet activation and in vivo thrombosis and homeostasis. 4,5 In tumors, only one study has found that VPS33B serves as an important tumor suppressor in hepatocarcinogenesis.…”