1. Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis.
- Author
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Gong Y, Krakow D, Marcelino J, Wilkin D, Chitayat D, Babul-Hirji R, Hudgins L, Cremers CW, Cremers FP, Brunner HG, Reinker K, Rimoin DL, Cohn DH, Goodman FR, Reardon W, Patton M, Francomano CA, and Warman ML more...
- Subjects
- Adolescent, Animals, Carrier Proteins, Cats, Chickens, Chromosome Mapping, Female, Finger Joint abnormalities, Gene Expression Regulation, Developmental, Genetic Markers, Gorilla gorilla, Heterozygote, Humans, Joints physiology, Male, Mice, Molecular Sequence Data, Morphogenesis, Sequence Analysis, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Swine, Xenopus laevis, Zebrafish, Abnormalities, Multiple genetics, Joints abnormalities, Mutation, Proteins genetics, Synostosis genetics
- Abstract
The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGFbeta-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG 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 synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation and suggest that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species. more...
- Published
- 1999
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