FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2029369507> ?p ?o ?g. }

• W2029369507 endingPage "396" @default.
• W2029369507 startingPage "388" @default.
• W2029369507 abstract "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. 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. Brachydactyly is shortness of the fingers and/or toes (digits), usually inherited as a dominant trait. It most often occurs as an isolated physical feature but can also be part of a more complex set of anomalies such as a skeletal dysplasia or a congenital malformation syndrome. According to their pattern of skeletal hand malformation, the different isolated brachydactylies have been classified into the subtypes A–E.1Bell J On brachydactyly and symphalangism.in: Penrose, LS Treasury of human inheritance. Vol 5. Cambridge University Press, London, United Kingdom1951: 1-31Google ScholarBrachydactyly type B (BDB), the most severe form, is characterized by aplasia or hypoplasia of the distal and middle phalanges of digits II–V. In less severe cases, hypoplasia of the distal phalanx is associated with hypoplasia of the nails and fusion of distal interphalangeal joints. To date, heterozygous mutations in the gene encoding the receptor tyrosine kinase–like orphan receptor 2 (ROR2 [GenBank accession number NM_004560]) have been reported to be the cause of BDB1 (MIM 113000) in the majority of affected individuals. These mutations cluster in two regions, resulting in truncation of the receptor of either the N-terminal or C-terminal of the intracellular tyrosine kinase domain.2Oldridge M Fortuna AM Maringa M Propping P Mansour S Pollitt C DeChiara TM Kimble RB Valenzuela DM Yancopoulos GD et al.Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.Nat Genet. 2000; 24: 275-278Crossref PubMed Scopus (170) Google Scholar, 3Schwabe GC Tinschert S Buschow C Meinecke P Wolff G Gillessen-Kaesbach G Oldridge M Wilkie AOM Komec R Mundlos S Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.Am J Hum Genet. 2000; 67: 822-831Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar The patients described here were screened for mutations in ROR2, but no mutations were identified. ROR2-negative BDB has been described before, indicating genetic heterogeneity of the disorder, but the molecular basis in this group of patients was not known. Previous studies have shown that BMPR1B, the high-affinity receptor for GDF5, interacts with ROR2.4Sammar M Stricker S Schwabe GC Sieber C Hartung A Hanke M Oishi I Pohl J Minami Y Sebald W et al.Modulation of GDF5/BRI-b signalling through interaction with the tyrosine kinase receptor Ror2.Genes Cells. 2004; 9: 1227-1238Crossref PubMed Scopus (78) Google Scholar We therefore sequenced GDF5, BMPR1B, and the inhibitor of GDF5—NOGGIN (NOG [GenBank accession number NM_005450])—in all ROR2-negative subjects. Informed consent for genetic analyses was obtained from all patients or their legal guardians. Molecular testing was performed on purified genomic DNA obtained from venous blood samples. The primer sequences and PCR conditions for the molecular testing can be found elsewhere (for ROR2,3Schwabe GC Tinschert S Buschow C Meinecke P Wolff G Gillessen-Kaesbach G Oldridge M Wilkie AOM Komec R Mundlos S Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.Am J Hum Genet. 2000; 67: 822-831Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar for GDF5,5Schwabe GC Turkmen S Leschik G Palanduz S Stover B Goecke TO Mundlos S Brachydactyly type C caused by a homozygous missense mutation in the prodomain of CDMP1.Am J Med Genet A. 2004; 124: 356-363Crossref Scopus (51) Google Scholar and for BMPR1B6Lehmann K Seemann P Stricker S Sammar M Meyer B Suring K Majewski F Tinschert S Grzeschik KH Muller D et al.Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.Proc Natl Acad Sci USA. 2003; 100: 12277-12282Crossref PubMed Scopus (123) Google Scholar). The NOG-coding region was amplified in two overlapping segments, with use of the following primer pairs: 1-1 forward (5′-CTCGGCGTGCTCTCCTC-3′) and 1-1 reverse (5′-GCTTAGGCGCTGCTTCTTG-3′), which produced a PCR product of 476 bp, and 1-2 forward (5′-ACCTGGCGGAGCTGGAC-3′) and 1-2 reverse (5′-GAACTGGTTGGAGGCGG-3′), which produced a PCR product of 479 bp. PCR conditions can be obtained on request. Sequencing was done using the ABI Prism BigDye Terminator Sequencing Kit (Applied Biosystems), with PCR primers used as sequencing primers. Products were evaluated on an automated capillary sequencer (Applied Biosystems). We discovered heterozygosity for five different missense mutations in NOG in six familial cases (c.103C→G [P35A], c.103C→T [P35S], c.106G→C [A36P], c.142G→A [E48K], and c.559 C→T [P187S]), originating from Germany, Turkey, Denmark, Iran, and the United Kingdom. In one patient from North America, a de novo mutation, c.499C→G (R167G), confirmed by molecular testing in the unaffected parents, was detected. Heterozygous mutations in NOG have been reported elsewhere to be associated with several human disorders characterized by abnormal joints, including proximal symphalangism (SYM1 [MIM 185800]), tarsal-carpal coalition syndrome (TCC [MIM 186570]), multiple synostosis syndrome (SYNS1 [MIM 186500]), and stapes ankylosis with broad thumb and toes without symphalangism (MIM 184460).7Gong Y Krakow D Marcelino J Wilkin D Chitayat D Babul-Hirji R Hudgins L Cremers CW Cremers FP Brunner HG et al.Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis.Nat Genet. 1999; 21: 302-304Crossref PubMed Scopus (261) Google Scholar, 8Dixon ME Armstrong P Stevens DB Bamshad M Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism.Genet Med. 2001; 3: 349-353Crossref PubMed Scopus (64) Google Scholar, 9Marcelino J Sciortino CM Romero MF Ulatowski LM Ballock RT Economides AN Eimon PM Harland RM Warman ML Human disease-causing NOG missense mutations: effects on noggin secretion, dimer formation, and bone morphogenetic protein binding.Proc Natl Acad Sci USA. 2001; 98: 11353-11358Crossref PubMed Scopus (70) Google Scholar, 10Brown DJ Kim TB Petty EM Downs CA Martin DM Strouse PJ Moroi SE Milunsky JM Lesperance MM Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin.Am J Hum Genet. 2002; 71: 618-624Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar In five of the six families, DNA samples from additional family members were available for NOG screening. Sequence analysis demonstrated that the NOG mutations segregated with the phenotype with an autosomal dominant inheritance in a total of 24 meioses (fig. 1). All patients exhibited a distinct clinical phenotype, featuring absent/hypoplastic terminal and/or middle phalanges with an amputation-like phenotype similar to that observed in BDB (fig. 2A). In most patients, fingers IV and V showed a severe transverse distal reduction, and fingers II and III were less severely affected. In those fingers in which the distal phalanges were present, abnormal proximal interphalangeal joints were observed, which resulted in the inability to bend the fingers and in missing flexion creases. The most severely affected patients showed a BDB phenotype, with an entire aplasia of the distal and middle phalanges of digits II–V. A few of the patients had a milder phenotype, featuring hypoplastic distal phalanges II–V. We categorized the phenotypic expression observed in the patients’ hands into three groups: mild (distal phalanges of fingers II-V present but hypoplastic); intermediate (absent distal and sometimes middle phalanges of ulnar rays [fingers IV and V more severely affected than fingers II and III]), and severe (distal and sometimes middle phalanges of fingers II–V absent) (table 1).Figure 2Clinical phenotypes caused by the NOG mutations. In panel A, pictures in each vertical group belong to one patient; corresponding mutations are depicted above. In hands, note variable terminal deficiency of fingers. Terminal deficiency—particularly of phalanges IV and V, with a milder involvement of distal phalanges II and III (“intermediate” BDB in table 1)—are depicted in patients 1, 2, 4, and 6. Severely affected hands with absent distal and middle phalanges of fingers II–V (“severe” BDB in table 1) are shown in patient 3. Hypoplastic but present distal phalanges of fingers (“mild” BDB in table 1) are shown in patient 5. Note proximally set thumbs and additional cutaneous syndactyly in some affected hands. Radiographs show proximal SYM of fingers II–V, present in fingers consisting of at least two phalanges. Fusion of carpal bones is a further typical feature (in patient 1, note the atypically configured carpal bones with fusion of hamate, capitate, trapezoid, and trapezium). Shortened metacarpal bones I can be seen in most affected hands. In feet, toes are similarly affected (patient 6 had surgical removal of toes). B, Magnifications. a, Proximal SYM. b, Proximal and distal SYM, as observed in patient 5. c, Accelerated development of carpal bones and the proximal epiphysis of metacarpal bone I in a 6-mo-old child. Note narrowed distance between hamate and triquetrum, indicating a future fusion. d, Absent flexion creases due to the fused interphalangeal joints. e, Symmetric constriction rings in the middle of both second toes in patient 2, imitating a condition caused by amniotic bands.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Summary of the Clinical Data Correlated with the Identified NOG MutationsIncidence of PhenotypeBDBMutationMildaDistal phalanges and nails present, but hypoplastic in fingers II–V.IntermediatebAbsent distal and sometimes middle phalanges of fingers IV and/or V (more affected by BDB than are fingers II and III).SeverecAbsent distal (and middle) phalanges of fingers II–V.Distal SYMCarpal CoalitionShortened MC IdMC I=metacarpal bone I.Cutaneous SyndactylyP35A2/1210/128/88/88/8P35S3/63/65/5eTwo of five are x-rays of a 6-mo-old child; both hands showed an accelerated carpal bone age of ∼2.5 years.5/54/6A36P4/42/20/20/4E48K2/42/4+2/22/20/4R167G2/21/2fIn x-rays of a newborn, both hands showed an accelerated carpal bone age of ∼6 mo.0/20/2P187S3/63/6+2/21/2gAdditionally shortened MC IV and V.6/6Note.—All subjects had proximal SYM. Each hand of the patients was counted separately. Radiographs were not available for all affected individuals. For each of the listed features, the observed phenotypes refer to the total number of available data (as indicated after the slash).a Distal phalanges and nails present, but hypoplastic in fingers II–V.b Absent distal and sometimes middle phalanges of fingers IV and/or V (more affected by BDB than are fingers II and III).c Absent distal (and middle) phalanges of fingers II–V.d MC I=metacarpal bone I.e Two of five are x-rays of a 6-mo-old child; both hands showed an accelerated carpal bone age of ∼2.5 years.f In x-rays of a newborn, both hands showed an accelerated carpal bone age of ∼6 mo.g Additionally shortened MC IV and V. Open table in a new tab Note.— All subjects had proximal SYM. Each hand of the patients was counted separately. Radiographs were not available for all affected individuals. For each of the listed features, the observed phenotypes refer to the total number of available data (as indicated after the slash). In those individuals in whom fingers II–V consisted of two or three phalanges, a fusion of the proximal interphalangeal joints (SYM1) was typically present. Fusion of the distal interphalangeal joints (distal symphalangism [SYM]), similar to fingers observed in patients with ROR2 mutations associated with a mild phenotype, was additionally observed in patients showing a mild BDB who carried an E48K or a P187S NOG mutation. The available radiographs of the adult patients’ hands and feet verified the phalangeal joint fusions. In addition, they revealed a coalition of carpal and tarsal bones leading in the hands to a small metacarpus with abnormally configured bones. In two children, we observed an acceleration of bone age. In a newborn girl, an accelerated development of carpal bones of ∼6 mo was present (radiographs not shown). In a 6-mo-old child, the status of carpal bones corresponded to the development of a 3-year-old child (fig. 2B [magnification in fig. 2c]). In the latter case, the distance between the hamate and the triquetral bones was narrowed, indicating a future fusion of those two bones, and the proximal epiphysis of metacarpal bone I was unusually formed, caused by an accelerated ossification. The thumbs were proximally set in the majority of patients, because of short first metacarpal bones. Cutaneous syndactyly, particularly between fingers II and III and between fingers III and IV, was observed as an associated feature. The patients’ feet were affected in a similar way. Toes II–V showed terminal deficiency to a variable degree, and they were stiffened if they consisted of more than one phalanx. The big toes appeared normal. Interestingly, we observed symmetric constrictions in the middle of both second toes in one of the described patients (fig. 2B [magnification in fig. 2e]). This phenotype imitates a condition typically caused by amniotic bands. Sensorineural hearing loss and farsightedness were observed in a few patients. The overall clinical manifestations of the investigated patients are summarized in table 1. Our clinical data describe a new subtype of brachydactyly characterized by hypoplasia/aplasia of distal phalanges in combination with (1) SYM, (2) fusion of carpal/tarsal bones, and (3) partial cutaneous syndactyly. We propose to call this type of hand/foot malformation “brachydactyly type B2” (BDB2), because of its striking similarity to BDB1. A clinical description of a family published by Herrmann11Herrmann J Symphalangism and brachydactyly syndrome: report of the WL symphalangism-brachydactyly syndrome.Birth Defects Orig Artic Ser. 1974; 10: 23-53PubMed Google Scholar and some of the patients reported by Maroteaux et al.12Maroteaux P Bouvet JP Briard ML [Multiple synostosis disease.].Nouv Presse Med. 1972; 1: 3041-3047PubMed Google Scholar seem to have a comparable phenotype, with variable brachydactyly and associated joint fusions. We excluded a NOG mutation in BDB-affected family 3 described by Oldridge et al.13Oldridge M Temple IK Santos HG Gibbons RJ Mustafa Z Chapman KE Loughlin J Wilkie AOM Brachydactyly type B: linkage to chromosome 9q22 and evidence for genetic heterogeneity.Am J Hum Genet. 1999; 64: 578-585Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar in 1999; the family was also negative for mutations in ROR2, indicating that at least one further locus for BDB exists. In the patients presented here, the P35S mutation in NOG was identified in two unrelated individuals, whereas each of the changes P35A, A36P, E48K, R167G, and P187S was detected once. The mutation R167G occurred de novo. All detected changes cosegregate with the BDB2 phenotype, affect highly conserved amino acids of NOG (data not shown), are not present in 200 control individuals, and are thus likely to represent pathogenic mutations. Overall, we identified six different NOG mutations. The mutations altering codons 36, 167, and 187 are novel, whereas NOG mutations affecting codons 35 and 48 have been described elsewhere in association with abnormal joint fusions in hands and feet.7Gong Y Krakow D Marcelino J Wilkin D Chitayat D Babul-Hirji R Hudgins L Cremers CW Cremers FP Brunner HG et al.Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis.Nat Genet. 1999; 21: 302-304Crossref PubMed Scopus (261) Google Scholar, 8Dixon ME Armstrong P Stevens DB Bamshad M Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism.Genet Med. 2001; 3: 349-353Crossref PubMed Scopus (64) Google Scholar, 14Kosaki K Sato S Hasegawa T Matsuo N Suzuki T Ogata T Premature ovarian failure in a female with proximal symphalangism and Noggin mutation.Fertil Steril. 2004; 81: 1137-1139Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar In a woman carrying the same E48K mutation, an association of premature ovarian failure, proximal and distal SYM, TCC, and shortness of single fingers and toes with hypoplastic fingernails was reported.14Kosaki K Sato S Hasegawa T Matsuo N Suzuki T Ogata T Premature ovarian failure in a female with proximal symphalangism and Noggin mutation.Fertil Steril. 2004; 81: 1137-1139Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar The P35S change is listed as a SNP, but screening of 200 control individuals did not show any alteration at codon 35 in NOG. Furthermore, the P35S mutation was identified in an Italian family with SYM1.15Mangino M Flex E Digilio MC Giannotti A Dallapiccola B Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism.Hum Mutat. 2002; 19: 308Crossref PubMed Scopus (29) Google Scholar In the clinical description of an affected father and son, additional hypoplasia of distal phalanges was mentioned. Another mutation at position 35, a change from proline to arginine (P35R), described twice elsewhere, resulted either in isolated SYM1 or in TCC.7Gong Y Krakow D Marcelino J Wilkin D Chitayat D Babul-Hirji R Hudgins L Cremers CW Cremers FP Brunner HG et al.Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis.Nat Genet. 1999; 21: 302-304Crossref PubMed Scopus (261) Google Scholar, 8Dixon ME Armstrong P Stevens DB Bamshad M Identical mutations in NOG can cause either tarsal/carpal coalition syndrome or proximal symphalangism.Genet Med. 2001; 3: 349-353Crossref PubMed Scopus (64) Google Scholar These data support an essential function of the amino acid P35 in NOG. NOG is an extracellular antagonist of bone morphogenetic proteins (BMPs) and growth-differentiation factors (GDFs). The BMP family of secreted molecules has multiple roles in early embryonal development and particularly in skeletogenesis. BMPs and GDFs promote the proliferation and differentiation of mesenchymal precursor cells into chondrocytes and/or osteoblasts and initiate and control the formation of joints at specific regions.16Brunet LJ McMahon JA McMahon AP Harland RM Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton.Science. 1998; 280: 1455-1457Crossref PubMed Scopus (668) Google Scholar GDF5 plays an essential role in chondrocyte differentiation and in the fine tuning of phalangeal development.17Francis-West PH Abdelfattah A Chen P Allen C Parish J Ladher R Allen S MacPherson S Luyten FP Archer CW Mechanisms of GDF-5 action during skeletal development.Development. 1999; 126: 1305-1315PubMed Google Scholar, 18Storm EE Kingsley DM GDF5 coordinates bone and joint formation during digit development.Dev Biol. 1999; 209: 11-27Crossref PubMed Scopus (315) Google Scholar This complex regulation of BMP and GDF activity is specifically modulated by inhibition through the presence of several BMP antagonists, like NOG.19Francis-West PH Parish J Lee K Archer CW BMP/GDF-signalling interactions during synovial joint development.Cell Tissue Res. 1999; 296: 111-119Crossref PubMed Scopus (149) Google Scholar, 20Nifuji A Noda M Coordinated expression of noggin and bone morphogenetic proteins (BMPs) during early skeletogenesis and induction of noggin expression by BMP-7.J Bone Miner Res. 1999; 14: 2057-2066Crossref PubMed Scopus (54) Google Scholar The proteins of the BMP family exert their effect via two different types of BMP receptors: the type I (BMPR1B and BMPR1A) and the type II receptors. The affinities of ligands toward the BMP receptors differ. For example, GDF5 binds with a high affinity to BMPR1B, whereas BMP2 can bind to both BMPR1A and BMPR1B. After ligand binding, the BMP type I receptors get activated through the BMP type II receptor by a phosphorylation process leading to intracellular downstream signaling of SMAD (homolog of mothers against decapentaplegic, Drosophila) proteins and the MAP (mitogen-activated protein) kinase pathway.21Gilboa L Nohe A Geissendorfer T Sebald W Henis YI Knaus P Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors.Mol Biol Cell. 2000; 11: 1023-1035Crossref PubMed Scopus (243) Google Scholar, 22Nohe A Keating E Knaus P Petersen NO Signal transduction of bone morphogenetic protein receptors.Cell Signal. 2004; 16: 291-299Crossref PubMed Scopus (430) Google Scholar NOG binds to BMPs and thereby masks the BMP type I and II receptor–binding sites of certain BMPs and GDF5,23Balemans W Van Hul W Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators.Dev Biol. 2002; 250: 231-250Crossref PubMed Google Scholar, 24Groppe J Greenwald J Wiater E Rodriguez-Leon J Economides AN Kwiatkowski W Affolter M Vale WW Belmonte JC Choe S Structural basis of BMP signalling inhibition by the cystine knot protein Noggin.Nature. 2002; 420: 636-642Crossref PubMed Scopus (406) Google Scholar and, subsequently, no signaling is initiated.25Nishitoh H Ichijo H Kimura M Matsumoto T Makishima F Yamaguchi A Yamashita H Enomoto S Miyazono K Identification of type I and type II serine/threonine kinase receptors for growth/differentiation factor-5.J Biol Chem. 1996; 271: 21345-21352Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, 26Kirsch T Nickel J Sebald W BMP-2 antagonists emerge from alterations in the low-affinity binding epitope for receptor BMPR-II.EMBO J. 2000; 19: 3314-3324Crossref PubMed Scopus (201) Google Scholar, 27Massague J Chen Y-G Controlling TGF-β signaling.Genes Dev. 2000; 14: 627-644PubMed Google Scholar To elucidate the possible molecular mechanisms by which these newly identified mutations in NOG may act to produce BDB in combination with joint fusions, we superimposed the altered amino acid residues on the known three-dimensional structure of human NOG (fig. 3). The structure of the complex has been modeled by alignment of the sequence of human GDF5 on the Protein Data Bank (PDB) coordinates of the BMP7 dimer within the NOG:BMP7 structure (PDB entry 1M4U), which was solved by x-ray crystallography.24Groppe J Greenwald J Wiater E Rodriguez-Leon J Economides AN Kwiatkowski W Affolter M Vale WW Belmonte JC Choe S Structural basis of BMP signalling inhibition by the cystine knot protein Noggin.Nature. 2002; 420: 636-642Crossref PubMed Scopus (406) Google Scholar, 28Schreuder H Liesum A Pohl J Kruse M Koyama M Crystal structure of recombinant human growth and differentiation factor 5: evidence for interaction of the type I and type II receptor-binding sites.Biochem Biophys Res Commun. 2005; 329: 1076-1086Crossref PubMed Scopus (45) Google Scholar The type I and II receptor–binding sites have been determined using PP_SITE.29Gao Y Lai L Structure-based method for analyzing protein-protein interfaces.J Mol Model. 2004; 10: 44-54Crossref PubMed Scopus (86) Google Scholar The estimated reduction of free-binding energy was calculated for each NOG mutant by FOLD-X.29Gao Y Lai L Structure-based method for analyzing protein-protein interfaces.J Mol Model. 2004; 10: 44-54Crossref PubMed Scopus (86) Google Scholar, 30Guerois R Nielsen JE Serrano L Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations.J Mol Biol. 2002; 320: 369-387Crossref PubMed Scopus (1216) Google Scholar The free-binding energy of the complex formation of wild-type (WT) NOG and GDF5 was calculated and set to 100% (table 2). The comparison of the free-binding energy of WT NOG versus the NOG mutants to GDF5 shows that the mutation P35R, which is known to be associated with SYM1 or TCC (but not BDB), has the highest loss of free-binding energy (51%). The BDB2-associated mutations showed a less severe reduction in free-binding energy. The mutations P35A resulted in 14% and P35S in 31% relative loss of free-binding energy; the mutation P187S resulted in 16% loss of free-binding energy. The remainder of BDB2-related mutations at positions A36, E48, and R167 led to reductions of <6%. Thus, the behavior of the majority of BDB2 mutations is similar to that of WT NOG, and BDB2 mutations are able to antagonize GDF5 function. Our data indicate that a loss of NOG-GDF5 inhibition is not sufficient to explain the BDB2 phenotype.Table 2Calculated Changes of Free Energy of Double Dimer Binding of NOG and GDF5Phenotype and MutationdG (kcal/mol)dG (%)ddG (%)Reference: WT Nog−42.001000SYM1/TCC: P35R−20.704951BDB2: P35A−36.008614 P35S−29.006931 A36P−41.20982 E48K−41.55991 R167G−39.30946 P187S−35.108416Note.—Free-binding energy (dG) was calculated for binding of WT NOG or indicated NOG mutants to WT GDF5 by FOLD-X. Binding of WT NOG to WT GDF5 was set to 100% and was used as a reference for the calculated reduction of binding energy (ddG) of the NOG mutations. The SYM1/TCC (without BDB2)–associated mutation P35R resulted in the highest loss of free-binding energy (51%). In comparison, all BDB2-associated mutations showed less reduction of free-binding energy (1%–31%). Open table in a new tab Note.— Free-binding energy (dG) was calculated for binding of WT NOG or indicated NOG mutants to WT GDF5 by FOLD-X. Binding of WT NOG to WT GDF5 was set to 100% and was used as a reference for the calculated reduction of binding energy (ddG) of the NOG mutations. The SYM1/TCC (without BDB2)–associated mutation P35R resulted in the highest loss of free-binding energy (51%). In comparison, all BDB2-associated mutations showed less reduction of free-binding energy (1%–31%). Interestingly, the identified BDB2-associated mutations in NOG do not cluster on a certain domain; rather, they affect three independent regions: (1) the dimerization domain (P187, marked in blue in fig. 3), (2) the site that covers the type I receptor pocket in BMPs/GDFs (P35 and A36, marked in red in fig. 3), and (3) the site that covers the type II receptor pocket (E48 and R167, marked in yellow in fig. 3). NOG and GDF5 are dimers linked by a disulfide bridge. The C-terminal region of NOG contains a cysteine-knot motif of nine cysteine residues that is important for disulfide-bond formation and dimerization.24Groppe J Greenwald J Wiater E Rodriguez-Leon J Economides AN Kwiatkowski W Affolter M Vale WW Belmonte JC Choe S Structural basis of BMP signalling inhibition by the cystine knot protein Noggin.Nature. 2002; 420: 636-642Crossref PubMed Scopus (406) Google Scholar One of the BDB2-causing NOG mutations (P187S) lies in the critical dimerization interface of NOG. This alteration destabilizes the NOG-homodimer binding, possibly influencing the overall structural integrity of the NOG-BMP complex formation. This was confirmed by western-blot analysis of supernatants of" @default.
• W2029369507 created "2016-06-24" @default.
• W2029369507 creator A5001962694 @default.
• W2029369507 creator A5006658158 @default.
• W2029369507 creator A5015376243 @default.
• W2029369507 creator A5023743496 @default.
• W2029369507 creator A5043343376 @default.
• W2029369507 creator A5043530715 @default.
• W2029369507 creator A5044006088 @default.
• W2029369507 creator A5056974831 @default.
• W2029369507 creator A5062453284 @default.
• W2029369507 creator A5077826397 @default.
• W2029369507 creator A5078809633 @default.
• W2029369507 creator A5084433109 @default.
• W2029369507 creator A5090032580 @default.
• W2029369507 date "2007-08-01" @default.
• W2029369507 modified "2023-10-01" @default.
• W2029369507 title "A New Subtype of Brachydactyly Type B Caused by Point Mutations in the Bone Morphogenetic Protein Antagonist NOGGIN" @default.
• W2029369507 cites W1486612810 @default.
• W2029369507 cites W1520481055 @default.
• W2029369507 cites W1608507417 @default.
• W2029369507 cites W1639188211 @default.
• W2029369507 cites W1923939500 @default.
• W2029369507 cites W1966414415 @default.
• W2029369507 cites W1968609694 @default.
• W2029369507 cites W1969880631 @default.
• W2029369507 cites W1974032064 @default.
• W2029369507 cites W1974921930 @default.
• W2029369507 cites W1979366468 @default.
• W2029369507 cites W1988165866 @default.
• W2029369507 cites W1988911192 @default.
• W2029369507 cites W1990409947 @default.
• W2029369507 cites W2015160990 @default.
• W2029369507 cites W2015272152 @default.
• W2029369507 cites W2035653490 @default.
• W2029369507 cites W2040356668 @default.
• W2029369507 cites W2041645520 @default.
• W2029369507 cites W2041745288 @default.
• W2029369507 cites W2052071684 @default.
• W2029369507 cites W2068710873 @default.
• W2029369507 cites W2071251725 @default.
• W2029369507 cites W2072438889 @default.
• W2029369507 cites W2078143938 @default.
• W2029369507 cites W2085344957 @default.
• W2029369507 cites W2090778914 @default.
• W2029369507 cites W2092387745 @default.
• W2029369507 cites W2093271566 @default.
• W2029369507 cites W2103262612 @default.
• W2029369507 cites W2110588967 @default.
• W2029369507 cites W2119391334 @default.
• W2029369507 cites W2122619315 @default.
• W2029369507 cites W2124870028 @default.
• W2029369507 cites W2148965620 @default.
• W2029369507 cites W2150776265 @default.
• W2029369507 cites W2232497098 @default.
• W2029369507 cites W2276473879 @default.
• W2029369507 cites W2994595875 @default.
• W2029369507 cites W4296588288 @default.
• W2029369507 doi "https://doi.org/10.1086/519697" @default.
• W2029369507 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/1950796" @default.
• W2029369507 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/17668388" @default.
• W2029369507 hasPublicationYear "2007" @default.
• W2029369507 type Work @default.
• W2029369507 sameAs 2029369507 @default.
• W2029369507 citedByCount "105" @default.
• W2029369507 countsByYear W20293695072012 @default.
• W2029369507 countsByYear W20293695072013 @default.
• W2029369507 countsByYear W20293695072014 @default.
• W2029369507 countsByYear W20293695072015 @default.
• W2029369507 countsByYear W20293695072016 @default.
• W2029369507 countsByYear W20293695072017 @default.
• W2029369507 countsByYear W20293695072018 @default.
• W2029369507 countsByYear W20293695072019 @default.
• W2029369507 countsByYear W20293695072020 @default.
• W2029369507 countsByYear W20293695072021 @default.
• W2029369507 countsByYear W20293695072022 @default.
• W2029369507 countsByYear W20293695072023 @default.
• W2029369507 crossrefType "journal-article" @default.
• W2029369507 hasAuthorship W2029369507A5001962694 @default.
• W2029369507 hasAuthorship W2029369507A5006658158 @default.
• W2029369507 hasAuthorship W2029369507A5015376243 @default.
• W2029369507 hasAuthorship W2029369507A5023743496 @default.
• W2029369507 hasAuthorship W2029369507A5043343376 @default.
• W2029369507 hasAuthorship W2029369507A5043530715 @default.
• W2029369507 hasAuthorship W2029369507A5044006088 @default.
• W2029369507 hasAuthorship W2029369507A5056974831 @default.
• W2029369507 hasAuthorship W2029369507A5062453284 @default.
• W2029369507 hasAuthorship W2029369507A5077826397 @default.
• W2029369507 hasAuthorship W2029369507A5078809633 @default.
• W2029369507 hasAuthorship W2029369507A5084433109 @default.
• W2029369507 hasAuthorship W2029369507A5090032580 @default.
• W2029369507 hasBestOaLocation W20293695071 @default.
• W2029369507 hasConcept C104317684 @default.
• W2029369507 hasConcept C125349252 @default.
• W2029369507 hasConcept C126322002 @default.
• W2029369507 hasConcept C144746171 @default.
• W2029369507 hasConcept C176944494 @default.
• W2029369507 hasConcept C2777871287 @default.

• next