Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis–renal dysfunction–cholestasis (ARC) syndrome

Gissen, Paul; Johnson, Colin A.; Morgan, Neil V.; Stapelbroek, Janneke M.; Forshew, Tim; Cooper, Wendy N.; McKiernan, Patrick; Klomp, Leo W. J.; Morris, Andrew A. M.; Wraith, J. Edmond; McClean, Patricia; Lynch, Sally Ann; Rj, Thompson; Lo, Bryan; Quarrell, Oliver; Rocco, Maja Di; Trembath, Richard C.; Mandel, Hannah; Wali, Sami; Karet, Fiona E.; Knisely, A. S.; Houwen, Roderick H. J.; Kelly, D A; Maher, Eamonn R.

doi:10.1038/ng1325

Cited by 298 publications

(288 citation statements)

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“…36 In some forms of intrahepatic cholestasis, g-GT expression along canaliculi appears disordered or lacking, and g-GTA in patients with those disorders does not rise despite cholestasis. 37,38 Our study demonstrates that variation in hepatobiliary CD10 expression may account for variation in conclusions drawn from previous studies of whether NEA can mark cholestasis. Swain et al 13 and Horvát-Karajz et al 14 concluded that NEA could mark cholestasis, whilst Janas et al 2 found no difference in NEA between cholestatic patients and controls.…”

Section: Nc1 Ags1 Ags2 Ags4 Ags5mentioning

confidence: 64%

Lack of hepatocellular CD10 along bile canaliculi is physiologic in early childhood and persistent in Alagille syndrome

Byrne

Meara

Rayner

et al. 2007

Laboratory Investigation

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Many tissues, including hepatobiliary cells, express neutral endopeptidase (CD10), encoded by MME. Serum neutral endopeptidase activity (NEA) has been recommended as a marker of cholestasis in adults but not in children with Alagille syndrome (AGS). We investigated ontogenic and disease-related differences in the expression of CD10. CD10 was found on canalicular surfaces of hepatocytes throughout the lobule in 16 adults and in 31 children aged Z24 months, with and without cholestasis, but not in 39 children aged o24 months, with and without cholestasis. Ten AGS children aged 2 months to 6 years lacked any canalicular CD10 expression. Cholangiocyte apices and/or intrasinusoidal granulocytes marked for CD10 in all subjects. Liver membrane fractions from a child with cholestasis aged o24 months and from 2 AGS patients aged 424 months contained reduced levels of CD10. In contrast, AGS children and all controls expressed CD10 similarly on granulocytes. MME mRNA was found in the liver of children aged o24 months and of adults, all with cholestasis, and of AGS patients. Granulocyte MME mRNA levels were similar among all study subjects; however, liver MME mRNA levels were 6-to 140-fold less than in normal adults in all cholestatic subjects, including AGS children. Methylation of the MME promoter was not detected in the liver of AGS children. In conclusion, hepatocytes in early childhood physiologically lack immunohistochemically detectable CD10. Reduced MME mRNA in AGS is not due to MME promoter methylation. Liver CD10 in childhood appears to undergo reduced synthesis or rapid degradation, which persists in AGS. Absence of CD10 expression thus may limit NEA as a marker of cholestasis in young patients and in AGS.

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Section: Nc1 Ags1 Ags2 Ags4 Ags5mentioning

confidence: 64%

Lack of hepatocellular CD10 along bile canaliculi is physiologic in early childhood and persistent in Alagille syndrome

Byrne

Meara

Rayner

et al. 2007

Laboratory Investigation

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“…The following NCBI RefSeq records were used for SPE-39 orthologues: human (NP_071350. endosomes, which are locations from which M6PR returns back to the Golgi complex (Klumperman et al, 1993;Hirst et al, 1998;Gissen et al, 2004;Tortorella et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…A missense mutation of the mouse VPS33A gene (buff) causes a mild platelet-storage pool deficiency and hypopigmentation due to defective melanosome biogenesis (Suzuki et al, 2003). Mutations in the human VPS33B gene cause arthrogryposis-renal dysfunction-cholestasis syndrome (Gissen et al, 2004), which is also usually associated with platelet dysfunction (Eastham et al, 2001). Both VPS33A and VPS33B are required during platelet formation; VPS33A is required for dense granule biogenesis, whereas VPS33B is required for ␣-granule biogenesis (Suzuki et al, 2003;Lo et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

SPE-39 Family Proteins Interact with the HOPS Complex and Function in Lysosomal Delivery

Zhu

Salazar²,

Zlatic³

et al. 2009

MBoC

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Yeast and animal homotypic fusion and vacuole protein sorting (HOPS) complexes contain conserved subunits, but HOPS-mediated traffic in animals might require additional proteins. Here, we demonstrate that SPE-39 homologues, which are found only in animals, are present in RAB5-, RAB7-, and RAB11-positive endosomes where they play a conserved role in lysosomal delivery and probably function via their interaction with the core HOPS complex. Although Caenorhabditis elegans spe-39 mutants were initially identified as having abnormal vesicular biogenesis during spermatogenesis, we show that these mutants also have disrupted processing of endocytosed proteins in oocytes and coelomocytes. C. elegans SPE-39 interacts in vitro with both VPS33A and VPS33B, whereas RNA interference of VPS33B causes spe-39-like spermatogenesis defects. The human SPE-39 orthologue C14orf133 also interacts with VPS33 homologues and both coimmunoprecipitates and cosediments with other HOPS subunits. SPE-39 knockdown in cultured human cells altered the morphology of syntaxin 7-, syntaxin 8-, and syntaxin 13-positive endosomes. These effects occurred concomitantly with delayed mannose 6-phosphate receptor-mediated cathepsin D delivery and degradation of internalized epidermal growth factor receptors. Our findings establish that SPE-39 proteins are a previously unrecognized regulator of lysosomal delivery and that C. elegans spermatogenesis is an experimental system useful for identifying conserved regulators of metazoan lysosomal biogenesis. INTRODUCTIONLysosome biogenesis is mediated by multiple vesicular budding and fusion events that deliver components between subcellular compartments (Luzio et al., 2003). In Saccharomyces cerevisiae, vesicular fusion at the vacuole (the yeast equivalent of lysosomes) requires the homotypic fusion and vacuole protein sorting (HOPS) complex, which regulates vesicle docking through its interaction with soluble N-ethylmaleimide-sensitive factor-attachment protein receptors (SNAREs) and the Rab protein Ypt7p Sato et al., 2000;Wurmser et al., 2000). The yeast HOPS complex contains class C Vps proteins Vps11p, Vps16p, Vps18p, and Vps33p (Rieder and Emr, 1997) and class B Vps proteins Vps39p and Vps41p (Seals et al., 2000;Wurmser et al., 2000). In addition to vesicular fusion at the vacuole, the class C Vps proteins also function in Golgi-to-endosome transport and other steps in vacuolar delivery pathways (Srivastava et al., 2000;Peterson and Emr, 2001;Subramanian et al., 2004;Peplowska et al., 2007). Involvement of the class C Vps proteins at multiple stages has also been reported in mammalian cells (Kim et al., 2003;Richardson et al., 2004). Vesicular trafficking to the lysosome has been extensively described in yeast (Bowers and Stevens, 2005), but it is also known that this process is more complex in metazoans (Dell'Angelica, 2004). Yeast only has lysosomes of a single type, whereas animals have lysosomes and lysosome-related organelles that are functionally diverse. This diversity is evident when comparing th...

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“…SNP genotyping studies Three affected members of the Omani family were genotyped with the Affymetrix 10k 2.0 SNP microarray (as described previously for other families 23 ). SNP genotyping studies in the four small families with a BBS10 mutation have been reported previously.…”

Section: Molecular Studiesmentioning

confidence: 99%

Autozygosity mapping of Bardet–Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10

et al. 2006

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Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by variable obesity, pigmentary retinopathy, polydactyly, mental retardation, hypogonadism and renal failure. In order to identify novel BBS loci we undertook autozygosity mapping studies using high-density SNP microarrays in consanguineous kindreds. We mapped a BBS locus to a 10.1 Mb region at 12q15-q21.2 in a large Omani BBS family (peak lod score 8.3 at h ¼ 0.0 for marker D12S1722) that contained the recently described BBS10 locus. Mutation analysis of candidate genes within the target interval, including the BBS10 gene, revealed a homozygous frameshift mutation in FLJ23560 and mutations were also detected in four smaller consanguineous families with regions of autozygosity at 12q21.2. These findings (a) confirm a previous report that FLJ23560 (BBS10) mutations are a significant cause of BBS, and (b) further demonstrate the utility of high-density SNP array mapping in consanguineous families for the mapping and identification of recessive disease genes.

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Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis–renal dysfunction–cholestasis (ARC) syndrome

Cited by 298 publications

References 27 publications

Lack of hepatocellular CD10 along bile canaliculi is physiologic in early childhood and persistent in Alagille syndrome

Lack of hepatocellular CD10 along bile canaliculi is physiologic in early childhood and persistent in Alagille syndrome

SPE-39 Family Proteins Interact with the HOPS Complex and Function in Lysosomal Delivery

Autozygosity mapping of Bardet–Biedl syndrome to 12q21.2 and confirmation of FLJ23560 as BBS10

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