A mutation in the heparin-binding site of noggin as a novel mechanism of proximal symphalangism and conductive hearing loss

•Nog with novel heterozygous p.R136C mutation was identified in patients with SYM1.•The noggin mutant was simulated to have reduced binding affinity to heparin.•Change in noggin–heparin interaction is suggested to underlie the clinical features. The access of bone morphogenetic protein (BMP) to the...

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Published inBiochemical and biophysical research communications Vol. 447; no. 3; pp. 496 - 502
Main Authors Masuda, Sawako, Namba, Kazunori, Mutai, Hideki, Usui, Satoko, Miyanaga, Yuko, Kaneko, Hiroki, Matsunaga, Tatsuo
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 09.05.2014
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Abstract •Nog with novel heterozygous p.R136C mutation was identified in patients with SYM1.•The noggin mutant was simulated to have reduced binding affinity to heparin.•Change in noggin–heparin interaction is suggested to underlie the clinical features. 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.
AbstractList 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.
•Nog with novel heterozygous p.R136C mutation was identified in patients with SYM1.•The noggin mutant was simulated to have reduced binding affinity to heparin.•Change in noggin–heparin interaction is suggested to underlie the clinical features. 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.
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.
Author Miyanaga, Yuko
Kaneko, Hiroki
Mutai, Hideki
Usui, Satoko
Namba, Kazunori
Matsunaga, Tatsuo
Masuda, Sawako
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Keywords HSPG
Docking simulation
BMP
DPOAE
TCS
NOG
DIP
Symphalangism
Conductive hearing loss
SYM1
ABR
CT
BMPR
TCC
PIP
Heparin
SYNS1
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Snippet •Nog with novel heterozygous p.R136C mutation was identified in patients with SYM1.•The noggin mutant was simulated to have reduced binding affinity to...
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...
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SubjectTerms Amino Acid Sequence
Amino Acid Substitution - genetics
Arginine - chemistry
Arginine - genetics
Asian Continental Ancestry Group - genetics
Binding Sites - genetics
BMP
Bone Morphogenetic Protein 7 - metabolism
Carrier Proteins - chemistry
Carrier Proteins - genetics
Carrier Proteins - metabolism
Child
Conductive hearing loss
Crystallography, X-Ray
Cysteine - chemistry
Cysteine - genetics
Docking simulation
Female
Finger Joint - abnormalities
Hearing Loss, Conductive - genetics
Heparin
Heparin - metabolism
Heterozygote
Humans
Japan
Joint Diseases - congenital
Joint Diseases - genetics
Molecular Sequence Data
Mutation, Missense
NOG
Pedigree
Signal Transduction
Symphalangism
Title A mutation in the heparin-binding site of noggin as a novel mechanism of proximal symphalangism and conductive hearing loss
URI https://dx.doi.org/10.1016/j.bbrc.2014.04.015
https://www.ncbi.nlm.nih.gov/pubmed/24735539
https://search.proquest.com/docview/1524176855
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