Details

Autor(en) / Beteiligte

• Marcelino, Jose
• Sciortino, Christopher M.
• Romero, Michael F.
• Ulatowski, Lynn M.
• Ballock, R. Tracy
• Economides, Aris N.
• Eimon, Peter M.
• Harland, Richard M.
• Warman, Matthew L.

Titel

Human Disease-Causing NOG Missense Mutations: Effects on Noggin Secretion, Dimer Formation, and Bone Morphogenetic Protein Binding

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2001-09, Vol.98 (20), p.11353-11358

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2001

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.