title: A mutation in the heparin-binding site of noggin as a novel mechanism of proximal symphalangism and conductive hearing loss.
abstract: The access of bone morphogenetic protein (BMP) to the BMP receptors on the cell surface is regulated by its antagonist noggin, which binds to heparan-sulfate proteoglycans on the cell surface. Noggin is encoded by NOG and mutations in the gene are associated with aberrant skeletal formation, such as in the autosomal dominant disorders proximal symphalangism (SYM1), multiple synostoses syndrome, Teunissen-Cremers syndrome, and tarsal-carpal coalition syndrome. NOG mutations affecting a specific function may produce a distinct phenotype. In this study, we investigated a Japanese pedigree with SYM1 and conductive hearing loss and found that it carried a novel heterozygous missense mutation of NOG (c.406C>T; p.R136C) affecting the heparin-binding site of noggin. As no mutations of the heparin-binding site of noggin have previously been reported, we investigated the crystal structure of wild-type noggin to investigate molecular mechanism of the p.R136C mutation. We found that the positively charged arginine at position 136 was predicted to be important for binding to the negatively charged heparan-sulfate proteoglycan (HSPG). An in silico docking analysis showed that one of the salt bridges between noggin and heparin disappeared following the replacement of the arginine with a non-charged cysteine. We propose that the decreased binding affinity of NOG with the p.R136C mutation to HSPG leads to an excess of BMP signaling and underlies the SYM1 and conductive hearing loss phenotype of carriers.
authors.affiliation: Department of Otorhinolaryngology, Institute for Clinical Research, National Mie Hospital, Tsu, Mie, Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Masuda
authors.affiliation: Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Tokyo Medical Center, Tokyo, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Namba
authors.affiliation: Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Tokyo Medical Center, Tokyo, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Mutai
authors.affiliation: Department of Otorhinolaryngology, Institute for Clinical Research, National Mie Hospital, Tsu, Mie, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Usui
authors.affiliation: Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Tokyo Medical Center, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Miyanaga
authors.affiliation: Department of Integrated Sciences in Physics and Biology, College of Humanities and Sciences, Nihon University, Tokyo, Japan. Electronic address: kaneko@phys.chs.nihon-u.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kaneko
authors.affiliation: Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Tokyo Medical Center, Tokyo, Japan. Electronic address: matsunagatatsuo@kankakuki.go.jp.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Matsunaga
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001120:Arginine / Q000737:chemistry / Q000235:genetics; D044466:Asian People / Q000235:genetics; D001665:Binding Sites / Q000235:genetics; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002648:Child; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D005260:Female; D005384:Finger Joint / Q000002:abnormalities*; D006314:Hearing Loss, Conductive / Q000235:genetics*; D006493:Heparin / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D007564:Japan; D007592:Joint Diseases / Q000151:congenital* / Q000235:genetics; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D015398:Signal Transduction; D000099176:Noggin Protein
chemical_list: D001120:Arginine; D055419:Bone Morphogenetic Protein 7; D002352:Carrier Proteins; D003545:Cysteine; D006493:Heparin; D000099176:Noggin Protein
keywords: BMP; Conductive hearing loss; Docking simulation; Heparin; NOG; Symphalangism