NOG and Proximal Symphalangism (SYM1), Multiple Synostosis (SYN1), Tarsal–Carpal Coalition, and Isolated Stapes Ankylosis

Abstract

Abstract Noggin (Nog) was first discovered as an important factor in brain development. The name reflects the observation that frog embryos injected with Nog mRNA grew exceptionally large heads. In Xenopus, Nog is able to mimic the activity of the Spemann organizer, which determines dorsal versus ventral fates in the gastrulating embryo. These and other studies demonstrated that Nog is a potent inhibitor of bone morphogenetic proteins (BMPs). Nog blocks the ability of BMPs to signal through cognate cell surface receptors by effectively masking the ligand-receptor–binding epitopes. Consequently, Nog has been widely used in experimental settings to negatively manipulate BMP signaling. Inactivation of Nog, on the other hand, results in excess BMP activity and, among many other developmental defects, in excess cartilage and a failure of joint formation. No human phenotype in association with a homozygous loss of function has been reported. However, four dominantly inherited conditions are associated with NOG mutations: proximal symphalangism (SYM1; OMIM 185800), multiple synostosis syndrome (SYN1; OMIM 186500), tarsal–carpal coalition (TCC; OMIM 186570), and isolated stapes ankylosis (OMIM 184460). All four conditions affect the development of the phalanges and/or joints resulting in brachydactyly and/or joint fusions. A second locus for proximal symphalangism (SYM2) has been shown to be associated with specific mutations in the gene encoding growth and differentiation factor 5 (GDF5).