Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome).
Johanson-Blizzard syndrome (OMIM 243800) is an autosomal recessive disorder that includes congenital exocrine pancreatic insufficiency, multiple malformations such as nasal wing aplasia, and frequent mental retardation. We mapped the disease-associated locus to chromosome 15q14-21.1 and identified mutations, mostly truncating ones, in the gene UBR1 in 12 unrelated families with Johanson-Blizzard syndrome. UBR1 encodes one of at least four functionally overlapping E3 ubiquitin ligases of the N-end rule pathway, a conserved proteolytic system whose substrates include proteins with destabilizing N-terminal residues. Pancreas of individuals with Johanson-Blizzard syndrome did not express UBR1 and had intrauterine-onset destructive pancreatitis. In addition, we found that Ubr1(-/-) mice, whose previously reported phenotypes include reduced weight and behavioral abnormalities, had an exocrine pancreatic insufficiency, with impaired stimulus-secretion coupling and increased susceptibility to pancreatic injury. Our findings indicate that deficiency of UBR1 perturbs the pancreas' acinar cells and other organs, presumably owing to metabolic stabilization of specific substrates of the N-end rule pathway.
Zenker
Martin
M
Institute of Human Genetics, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany. mzenker@humgenet.uni-erlangen.de
Mayerle
Julia
J
Lerch
Markus M
MM
Tagariello
Andreas
A
Zerres
Klaus
K
Durie
Peter R
PR
Beier
Matthias
M
Hülskamp
Georg
G
Guzman
Celina
C
Rehder
Helga
H
Beemer
Frits A
FA
Hamel
Ben
B
Vanlieferinghen
Philippe
P
Gershoni-Baruch
Ruth
R
Vieira
Marta W
MW
Dumic
Miroslav
M
Auslender
Ron
R
Gil-da-Silva-Lopes
Vera L
VL
Steinlicht
Simone
S
Rauh
Manfred
M
Shalev
Stavit A
SA
Thiel
Christian
C
Ekici
Arif B
AB
Winterpacht
Andreas
A
Kwon
Yong Tae
YT
Varshavsky
Alexander
A
Reis
André
A
D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D019767:Maxillofacial Abnormalities / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009666:Nose / Q000002:abnormalities; D010179:Pancreas / Q000201:enzymology* / Q000473:pathology; D010182:Pancreatic Diseases / Q000235:genetics* / Q000473:pathology; D013577:Syndrome; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics*
C113474:UBR1 protein, human; D044767:Ubiquitin-Protein Ligases