RGD Reference Report - VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5. - Rat Genome Database

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VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertase Pcsk5.

Authors: Szumska, D  Pieles, G  Essalmani, R  Bilski, M  Mesnard, D  Kaur, K  Franklyn, A  El Omari, K  Jefferis, J  Bentham, J  Taylor, JM  Schneider, JE  Arnold, SJ  Johnson, P  Tymowska-Lalanne, Z  Stammers, D  Clarke, K  Neubauer, S  Morris, A  Brown, SD  Shaw-Smith, C  Cama, A  Capra, V  Ragoussis, J  Constam, D  Seidah, NG  Prat, A  Bhattacharya, S 
Citation: Szumska D, etal., Genes Dev. 2008 Jun 1;22(11):1465-77. doi: 10.1101/gad.479408.
RGD ID: 11556208
Pubmed: PMID:18519639   (View Abstract at PubMed)
PMCID: PMC2418583   (View Article at PubMed Central)
DOI: DOI:10.1101/gad.479408   (Journal Full-text)

We have identified an ethylnitrosourea (ENU)-induced recessive mouse mutation (Vcc) with a pleiotropic phenotype that includes cardiac, tracheoesophageal, anorectal, anteroposterior patterning defects, exomphalos, hindlimb hypoplasia, a presacral mass, renal and palatal agenesis, and pulmonary hypoplasia. It results from a C470R mutation in the proprotein convertase PCSK5 (PC5/6). Compound mutants (Pcsk5(Vcc/null)) completely recapitulate the Pcsk5(Vcc/Vcc) phenotype, as does an epiblast-specific conditional deletion of Pcsk5. The C470R mutation ablates a disulfide bond in the P domain, and blocks export from the endoplasmic reticulum and proprotein convertase activity. We show that GDF11 is cleaved and activated by PCSK5A, but not by PCSK5A-C470R, and that Gdf11-deficient embryos, in addition to having anteroposterior patterning defects and renal and palatal agenesis, also have a presacral mass, anorectal malformation, and exomphalos. Pcsk5 mutation results in abnormal expression of several paralogous Hox genes (Hoxa, Hoxc, and Hoxd), and of Mnx1 (Hlxb9). These include known Gdf11 targets, and are necessary for caudal embryo development. We identified nonsynonymous mutations in PCSK5 in patients with VACTERL (vertebral, anorectal, cardiac, tracheoesophageal, renal, limb malformation OMIM 192350) and caudal regression syndrome, the phenotypic features of which resemble the mouse mutation. We propose that Pcsk5, at least in part via GDF11, coordinately regulates caudal Hox paralogs, to control anteroposterior patterning, nephrogenesis, skeletal, and anorectal development.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
VACTERL association  ISOPcsk5 (Mus musculus)11556208; 11556208DNA:mutation:exon:p.C470R(mouse)RGD 
VACTERL association  IAGP 11556208DNA:mutation:exon:p.C470R(mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pcsk5  (proprotein convertase subtilisin/kexin type 5)

Genes (Mus musculus)
Pcsk5  (proprotein convertase subtilisin/kexin type 5)

Genes (Homo sapiens)
PCSK5  (proprotein convertase subtilisin/kexin type 5)


Additional Information