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XB-ART-8378
Proc Natl Acad Sci U S A. September 25, 2001; 98 (20): 11353-8.

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 .


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.

PubMed ID: 11562478
PMC ID: PMC58733
Article link: Proc Natl Acad Sci U S A.
Grant support: AR 43527 NIAMS NIH HHS , GM 49346 NIGMS NIH HHS , HD 07014 NICHD NIH HHS

Genes referenced: mpv17 nog
Antibodies referenced:
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