Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome.
ARC syndrome (OMIM 208085) is an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity. Platelet dysfunction is common. Affected infants do not thrive and usually die in the first year of life. To elucidate the molecular basis of ARC, we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC. VPS33B encodes a homolog of the class C yeast vacuolar protein sorting gene, Vps33, that contains a Sec1-like domain important in the regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion.
Gissen
Paul
P
Section of Medical and Molecular Genetics, University of Birmingham, and Liver Unit, Birmingham Children's Hospital, UK.
Johnson
Colin A
CA
Morgan
Neil V
NV
Stapelbroek
Janneke M
JM
Forshew
Tim
T
Cooper
Wendy N
WN
McKiernan
Patrick J
PJ
Klomp
Leo W J
LW
Morris
Andrew A M
AA
Wraith
James E
JE
McClean
Patricia
P
Lynch
Sally A
SA
Thompson
Richard J
RJ
Lo
Bryan
B
Quarrell
Oliver W
OW
Di Rocco
Maja
M
Trembath
Richard C
RC
Mandel
Hanna
H
Wali
S
S
Karet
Fiona E
FE
Knisely
A S
AS
Houwen
Roderick H J
RH
Kelly
Deirdre A
DA
Maher
Eamonn R
ER
D001176:Arthrogryposis / Q000235:genetics*; D015153:Blotting, Western; D002460:Cell Line; D002779:Cholestasis / Q000235:genetics*; D002884:Chromosomes, Human, Pair 15; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics*; D008297:Male; D008561:Membrane Fusion / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D009154:Mutation; D010957:Plasmids; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D050600:SNARE Proteins; D013577:Syndrome; D033921:Vesicular Transport Proteins
D008565:Membrane Proteins; D011506:Proteins; D050600:SNARE Proteins; C411584:VPS33B protein, human; D033921:Vesicular Transport Proteins