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Letter
Nature Genetics  21, 302 - 304 (1999)
doi:10.1038/6821

Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis

Yaoqin Gong1, 2, Deborah Krakow3, 4, Jose Marcelino1, Douglas Wilkin5, David Chitayat6, Riyana Babul-Hirji6, Louanne Hudgins7, Cor W. Cremers8, Frans P.M. Cremers9, Han G. Brunner9, Kent Reinker10, David L. Rimoin3, 11, Daniel H. Cohn3, 11, Frances R. Goodman12, William Reardon12, Michael Patton13, Clair A. Francomano5 & Matthew L. Warman1

1  Department of Genetics and Center for Human Genetics, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio, USA.

2  Department of Genetics, Shandong Medical University , Jinan, P.R. China.

3  Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Burns and Allen Cedars-Sinai Research Institute, Cedars-Sinai Medical Center, Los Angeles, California , USA.

4  Departments of Obstetrics and Gynecology, Cedars-Sinai Medical Center and University of California, Los Angeles, California, USA.

5  National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland, USA .

6  Division of Genetics, Hospital for Sick Children, Toronto, Ontario, Canada.

7  Division of Medical Genetics, Children's Hospital and Medical Center, Seattle, Washingon, USA.

8  Department of Otorhinolaryngology, University of Nijmegen , Nijmegen, The Netherlands.

9  Department of Human Genetics, University of Nijmegen , Nijmegen, The Netherlands.

10  Department of Orthopedics, Shriner's Hospital, Honolulu, Hawaii, USA.

11  Department of Pediatrics, University of California , Los Angeles, California, USA.

12  Mothercare Unit of Clinical Genetics and Fetal Medicine, Institute of Child Health, London, UK.

13  S.W. Thames Regional Genetics Service, St. George's Hospital Medical School, London, UK.

Correspondence should be addressed to Matthew L. Warman mlw14@po.cwru.edu
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 gradients2. During mouse embryogenesis, Nog is expressed at multiple sites3, including developing bones4, 5. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton3, 4. 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 feature6, 7. 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.

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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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