Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis

The secreted polypeptide noggin (encoded by the Nog gene) binds and inactiv ates members of the transforming growth factor beta superfamily of signalli ng proteins (TGF beta-FMs), such as BMP4 (ref. 1). By diffusing through ext racellular matrices more efficiently than TGF beta-FMs, noggin may have a p rincipal role in creating morphogenic gradients2. During mouse embryogenesi s, Nog is expressed at multiple sites(3), including developing bones(4,5). Nog(-/-) mice die at birth from multiple defects that include bony fusion o f the appendicular skeleton(3,4). We have identified five dominant human NO G mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple syno stoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joi nt fusion as their principal feature(6,7). All seven NOG mutations alter ev olutionarily conserved amino CI acid residues. The findings reported here c onfirm that NOG is essential for joint formation and suggest that NOG requi rements during skeletogenesis differ between species and between specific s keletal elements within species.