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      Novel NOG (p.P42S) mutation causes proximal symphalangism in a four-generation Chinese family

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          Abstract

          Background

          Proximal symphalangism (SYM1; OMIM 185800), also called Cushing’s symphalangism, is an infrequent autosomal dominant disease. An SYM1 patient typically features variable fusion of proximal interphalangeal joints in the hands and feet.

          Methods

          We recruited a four-generation Chinese non-consanguineous family with SYM1. We examined their hands and feet using X-rays to confirm fusion of proximal interphalangeal joints. We evaluated their audiology using standard audiometric procedures and equipment. Then, we identified genetic variants using whole exome sequencing and validated mutations using Sanger sequencing. Mutation pathogenicity was analyzed with bioinformatics.

          Results

          Radiographs revealed proximal-joint fusion of fingers and toes in the patients. Two elderly individuals (II:1 and II:4) exhibited slight hearing loss. Additionally, we detected a novel heterozygous missense mutation in exon 1 of NOG (NM_005450) c.124C > T, p.(Pro42Ser) in all patients. This c.124C > T mutation is highly conserved across multiple species and the p.(Pro42Ser) variation is potentially highly pathogenic.

          Conclusion

          Our results suggest that heterozygous c.124C > T, p.(Pro42Ser) in NOG is a novel mutation that causes human SYM1 phenotype.

          Electronic supplementary material

          The online version of this article (10.1186/s12881-019-0864-1) contains supplementary material, which is available to authorized users.

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          Most cited references29

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          Structural basis of BMP signalling inhibition by the cystine knot protein Noggin.

          The interplay between bone morphogenetic proteins (BMPs) and their antagonists governs developmental and cellular processes as diverse as establishment of the embryonic dorsal-ventral axis, induction of neural tissue, formation of joints in the skeletal system and neurogenesis in the adult brain. So far, the three-dimensional structures of BMP antagonists and the structural basis for inactivation have remained unknown. Here we report the crystal structure of the antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors. The BMP-7-binding affinity of site-specific variants of Noggin is correlated with alterations in bone formation and apoptosis in chick limb development, showing that Noggin functions by sequestering its ligand in an inactive complex. The scaffold of Noggin contains a cystine (the oxidized form of cysteine) knot topology similar to that of BMPs; thus, ligand and antagonist seem to have evolved from a common ancestral gene.
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            Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis.

            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.
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              A new subtype of brachydactyly type B caused by point mutations in the bone morphogenetic protein antagonist NOGGIN.

              Brachydactyly type B (BDB) is characterized by terminal deficiency of fingers and toes, which is caused by heterozygous truncating mutations in the receptor tyrosine kinase-like orphan receptor 2 (ROR2) in the majority of patients. In a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis, we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG). In contrast to previously described loss-of-function mutations in NOG, which are known to cause a range of conditions associated with abnormal joint formation but without BDB, the newly identified BDB mutations do not indicate a major loss of function, as suggested by calculation of free-binding energy of the modeled NOG-GDF5 complex and functional analysis of the micromass culture system. Rather, they presumably alter NOG's ability to bind to BMPs and growth-differentiation factors (GDFs) in a subtle way, thus disturbing the intricate balance of BMP signaling. The combined features observed in this phenotypic subtype of BDB argue for a functional connection between BMP and ROR2 signaling and support previous findings of a modulating effect of ROR2 on the BMP-receptor pathway through the formation of a heteromeric complex of the receptors at the cell surface.
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                Author and article information

                Contributors
                SHswqz@126.com
                wx83905@163.com
                Journal
                BMC Med Genet
                BMC Med. Genet
                BMC Medical Genetics
                BioMed Central (London )
                1471-2350
                1 August 2019
                1 August 2019
                2019
                : 20
                : 133
                Affiliations
                [1 ]Department of Reproductive Medicine, Xiamen Maternity and Child Care Hospital, Xiamen, 361005 Fujian China
                [2 ]GRID grid.440323.2, Reproductive Medicine Center, , Affiliated Yantai Yuhuangding Hospital of Qingdao University, ; Yantai, 264000 Shandong China
                [3 ]ISNI 0000 0001 2264 7233, GRID grid.12955.3a, School of Pharmaceutical Sciences, , Xiamen University, ; Xiamen, 361005 Fujian China
                Author information
                http://orcid.org/0000-0001-5977-894X
                Article
                864
                10.1186/s12881-019-0864-1
                6670124
                31370824
                8d671bc4-6e6c-4b48-a6b9-bc52b1649647
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 21 February 2019
                : 23 July 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004572, National Health and Family Planning Commission of the People's Republic of China;
                Award ID: Grant No. KF201704
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100007129, Natural Science Foundation of Shandong Province;
                Award ID: Grant No. ZR2017LH012
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: Grant No. 81871200
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003392, Natural Science Foundation of Fujian Province;
                Award ID: Grant No. 2017D018
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Genetics
                proximal symphalangism,whole genome sequencing,missense mutation,nog
                Genetics
                proximal symphalangism, whole genome sequencing, missense mutation, nog

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