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Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis
Y Gong1, D Krakow, J Marcelino
1Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Ohio, USA.
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.
Insights
The secreted protein noggin is crucial for proper joint formation. Mutations in the NOG gene cause skeletal abnormalities like joint fusion in humans and mice.
Area of Science:
- Developmental biology
- Genetics
- Skeletal biology
Background:
- The secreted polypeptide noggin (Nog) inhibits transforming growth factor beta superfamily members (TGFbeta-FMs), like BMP4.
- Noggin's efficient diffusion suggests a role in creating morphogenic gradients during embryonic development.
- Nog gene expression occurs at multiple sites during mouse embryogenesis, including developing bones.
Purpose of the Study:
- To investigate the role of noggin in skeletal development and joint formation.
- To identify human NOG mutations associated with skeletal disorders.
Main Methods:
- Identification of dominant human NOG mutations in families with proximal symphalangism (SYM1) and multiple synostoses syndrome (SYNS1).
- Analysis of a de novo NOG mutation in a patient with unaffected parents.
- Examination of evolutionary conservation of mutated amino acid residues.
Main Results:
- Five dominant NOG mutations were identified in families with SYM1.
- A de novo NOG mutation was found in a patient with unaffected parents.
- A dominant NOG mutation was identified in a family with SYNS1.
- All seven identified NOG mutations affect evolutionarily conserved amino acid residues.
- Noggin is essential for joint formation, with mutations leading to joint fusion.
Conclusions:
- NOG mutations are causative for proximal symphalangism and multiple synostoses syndrome.
- The study confirms NOG's essential role in joint formation.
- Skeletal development requirements for noggin may vary across species and skeletal elements.