VACTERL/caudal regression/Currarino syndrome-like malformations in mice with mutation in the proprotein convertasePcsk5

Abstract

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 Pcsk5Vcc/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.[Keywords: Mouse; proprotein convertase; Gdf11; Hox; VACTERL] Supplemental material is available at http://www.genesdev.org.

Latent Transforming Growth Factor β-Binding Proteins-2 and -3 Inhibit the Proprotein Convertase 5/6A

“…Previous work (6,7) showed that PC5/6 is the proGdf11 convertase through cleavage at S1, and our present work further FIGURE 7. ProPC5/6A forms an intracellular complex with proGdf11, LTBP-2, or LTBP-3.…”

“…S1), which mostly occurs on the cell surface, where PC5/6A is anchored through its CRD that binds to heparan sulfate proteoglycans (HSPGs) (4). PC5/6 knock-out (KO) mice die at birth, and the newborn pups recapitulate all the phenotypes observed in mice lacking growth and differentiation factor 11 (Gdf11, also known as bone morphogenic protein 11 (BMP11)) (5), including an altered antero-posterior patterning with extra thoracic and lumbar vertebrae, lack of tail, and kidney agenesis (6,7). Gdf11 thus seems selectively cleaved by PC5/6 during development.…”

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

“…[137][138][139] ActRIIA and ActRIIB are recognized by several ligands, including GDF11, and have been involved in a variety of physiological functions, including bone homeostasis and age-related bone loss. 140 The trap ligand ACE-011 was made by fusing the extracellular domain of ActRIIA to the Fc domain of human IgG1.…”

Furin Is the Major Processing Enzyme of the Cardiac-specific Growth Factor Bone Morphogenetic Protein 10

“…These phenotypes emphasize the critical involvement of furin in cardiac development. Pcsk5 (PC5/6 gene) KO leads to death at birth with an altered antero-posterior patterning, including extra vertebrae, lack of tail, kidney agenesis, hemorrhages, collapsed alveoli, and retarded ossification, as well as heart ventricular-septal defects (5,6). Mice lacking Pcsk6 (PACE4 gene) KO survive to adulthood, and some develop incompletely penetrant left-right patterning defects combined with cyclopia, craniofacial, and cardiac malformations (7,8).…”