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Proc Natl Acad Sci U S A
2001 Sep 25;9820:11353-8. doi: 10.1073/pnas.201367598.
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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
.
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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.
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