Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
2001 Sep 25;9820:11353-8. doi: 10.1073/pnas.201367598.
Show Gene links
Show Anatomy links
Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding.
Marcelino J
,
Sciortino CM
,
Romero MF
,
Ulatowski LM
,
Ballock RT
,
Economides AN
,
Eimon PM
,
Harland RM
,
Warman ML
.
???displayArticle.abstract???
Secreted noggin protein regulates bone morphogenetic protein activity during development. In mice, a complete loss of noggin protein leads to multiple malformations including joint fusion, whereas mice heterozygous for Nog loss-of-function mutations are normal. In humans, heterozygous NOG missense mutations have been found in patients with two autosomal dominant disorders of joint development, multiple synostosis syndrome (SYNS1) and a milder disorder proximal symphalangism (SYM1). This study investigated the effect of one SYNS1 and two SYM1 disease-causing missense mutations on the structure and function of noggin. The SYNS1 mutation abolished, and the SYM1 mutations reduced, the secretion of functional noggin dimers in transiently transfected COS-7 cells. Coexpression of mutant noggin with wild-type noggin, to resemble the heterozygous state, did not interfere with wild-type noggin secretion. These data indicate that the human disease-causing mutations are hypomorphic alleles that reduce secretion of functional dimeric noggin. Therefore, we conclude that noggin has both species-specific and joint-specific dosage-dependent roles during joint formation. Surprisingly, in contrast to the COS-7 cell studies, the SYNS1 mutant was able to form dimers in Xenopus laevis oocytes. This finding indicates that there also exist species-specific differences in the ability to process mutant noggin polypeptides.
Noggin mutant proteins synthesized by Xenopus oocytes. Western blot analysis of Xenopus oocytes that were injected with capped RNA from pT7TS constructs containing SYM1-derived sequences (P223L and G189C) and SYNS1-derived sequence (W217G). Samples were subjected to nonreducing SDS/12% PAGE and immunodetected using an anti-noggin antibody. All noggin mutants form disulfide-bonded dimers, albeit with varying efficiency. Monomeric noggin migrates at 32 kDa, disulfide-bonded dimeric noggin migrates at 52 kDa, and a high molecular weight noggin aggregate (denoted by *) does not penetrate the separating gel.
Figure 8
Noggin mutant proteins are capable of inducing secondary axis formation in Xenopus embryos. Capped RNA (50 pg) synthesized from NOG constructs (WT or P223L) were injected into the marginal zone of the ventralblastomere of a four-cell embryo. Secondary axis formation is observed in both wild-type noggin (WT) and mutant noggin (P223L) capped RNA-injected embryos but not in uninjected embryos.
Baker,
Wnt signaling in Xenopus embryos inhibits bmp4 expression and activates neural development.
1999, Pubmed,
Xenbase
Baker,
Wnt signaling in Xenopus embryos inhibits bmp4 expression and activates neural development.
1999,
Pubmed
,
Xenbase
Brunet,
Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton.
1998,
Pubmed
Chang,
Xenopus GDF6, a new antagonist of noggin and a partner of BMPs.
1999,
Pubmed
,
Xenbase
Constam,
Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases.
1999,
Pubmed
Glinka,
Head induction by simultaneous repression of Bmp and Wnt signalling in Xenopus.
1997,
Pubmed
,
Xenbase
Gong,
Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis.
1999,
Pubmed
,
Xenbase
Groeneveld,
Bone morphogenetic proteins in human bone regeneration.
2000,
Pubmed
Hogan,
Bone morphogenetic proteins in development.
1996,
Pubmed
,
Xenbase
Kosaki,
Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development.
1999,
Pubmed
Krakow,
Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21-22.
1998,
Pubmed
McMahon,
Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite.
1998,
Pubmed
Meno,
lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal.
1998,
Pubmed
Merino,
Expression and function of Gdf-5 during digit skeletogenesis in the embryonic chick leg bud.
1999,
Pubmed
Mundlos,
Multiexon deletions in the type I collagen COL1A2 gene in osteogenesis imperfecta type IB. Molecules containing the shortened alpha2(I) chains show differential incorporation into the bone and skin extracellular matrix.
1996,
Pubmed
Polinkovsky,
Mutations in CDMP1 cause autosomal dominant brachydactyly type C.
1997,
Pubmed
Sarafova,
Three novel type I collagen mutations in osteogenesis imperfecta type IV probands are associated with discrepancies between electrophoretic migration of osteoblast and fibroblast collagen.
1998,
Pubmed
Sciortino,
Cation and voltage dependence of rat kidney electrogenic Na(+)-HCO(-)(3) cotransporter, rkNBC, expressed in oocytes.
1999,
Pubmed
,
Xenbase
Smith,
Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos.
1992,
Pubmed
,
Xenbase
Smith,
Secreted noggin protein mimics the Spemann organizer in dorsalizing Xenopus mesoderm.
1993,
Pubmed
,
Xenbase
Storm,
Limb alterations in brachypodism mice due to mutations in a new member of the TGF beta-superfamily.
1994,
Pubmed
Thomas,
Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1.
1997,
Pubmed
Van de Putte,
Osteogenesis in the interior of intramuscular implants of decalcified bone matrix.
1965,
Pubmed
Wozney,
Bone morphogenetic protein and bone morphogenetic protein gene family in bone formation and repair.
1998,
Pubmed
Zimmerman,
The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4.
1996,
Pubmed
,
Xenbase
Zou,
Requirement for BMP signaling in interdigital apoptosis and scale formation.
1996,
Pubmed
