Alternative titles; symbols
HGNC Approved Gene Symbol: NOG
SNOMEDCT: 702312009, 719305006, 770406002;
Cytogenetic location: 17q22 Genomic coordinates (GRCh38): 17:56,593,699-56,595,611 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q22 | Brachydactyly, type B2 | 611377 | Autosomal dominant | 3 |
| Multiple synostoses syndrome 1 | 186500 | Autosomal dominant | 3 | |
| Stapes ankylosis with broad thumbs and toes | 184460 | Autosomal dominant | 3 | |
| Symphalangism, proximal, 1A | 185800 | Autosomal dominant | 3 | |
| Tarsal-carpal coalition syndrome | 186570 | Autosomal dominant | 3 |
Using Xenopus noggin cDNA, Valenzuela et al. (1995) cloned full-length human genomic and cDNA NOG clones from a placenta genomic and a temporal cortex cDNA library. They also cloned a partial rat NOG cDNA from a brain cDNA library. Human NOG encodes a deduced 232-amino acid protein that shares 81% sequence identity with the Xenopus protein. In protein activity assays, human NOG appeared to share the inductive actions of Xenopus noggin during early embryogenesis. Northern blot analysis of adult rat tissues revealed predominant expression in most parts of the central nervous system, with especially high expression in mitral and tufted cells in the olfactory bulb, and in Purkinje cells in the cerebellum. Low or undetectable levels were found in peripheral nerve and nonneural tissues; in the latter tissues, detectable levels were found in lung, skeletal muscle, and skin.
Rudnik-Schoneborn et al. (2010) noted that the NOG gene contains a single exon.
Using fluorescence in situ hybridization, Valenzuela et al. (1995) showed that the NOG gene maps to chromosome 17q22. Both proximal symphalangism (SYM1A; 185800) and the multiple synostoses syndrome (SYNS1; 186500) were known to map to the same region. Gong et al. (1999) performed radiation hybrid mapping, placing NOG between genetic markers D17S790 and D17S794. Thus, NOG was a prime candidate gene for SYM1 and SYNS1 and prompted a mutation search.
Crystal Structure
Groppe et al. (2002) reported the crystal structure of the antagonist noggin bound to BMP7 (112267), which showed that noggin inhibits BMP signaling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors. The BMP binding affinity of site-specific variants of noggin was 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, Groppe et al. (2002) concluded that ligand and antagonist seem to have evolved from a common ancestral gene.
The bones of the developing limb bud are formed by condensations of chondrocytes followed by endochondral ossification. Postembryonic growth continues at the growth plates, at the ends of the bones. A series of inductive events determines the size and shape of individual limb skeletal elements. Many growth factors of the bone morphogenetic protein (BMP) family have been implicated in limb growth and patterning. The joints are formed after the initial cartilage condensation and are first recognized histologically by an increase in cell density. Cell death and cavitation follows. Growth/differentiation factor-5 (GDF5; 601146), a divergent member of the BMP family, is implicated in joint specification through its expression in prospective joints and its disruption in the 'brachypodism' mouse mutation. GDF5, also known as cartilage-derived morphogenetic protein-1, is mutant in several chondrodysplasias, such as the Grebe type of chondrodysplasia (200700) and the Hunter-Thompson type of acromesomelic dysplasia (201250), as well as in type C brachydactyly (113100). Brunet et al. (1998) showed that expression of the mouse noggin gene is essential for proper skeletal development. BMP activities are modulated not only through gene expression and protein processing, but also by interaction with antagonists such as noggin and chordin (603475). Excess BMP activity in noggin-null mice results in excess cartilage and failure to initiate joint formation. Murine noggin is expressed in condensing cartilage and immature chondrocytes, as are many BMPs. The excess BMP activity in the absence of noggin antagonism may enhance the recruitment of cells into cartilage, resulting in oversized growth plates. Chondrocytes are also refractory to joint-inducing positional cues. The noggin gene was first discovered as an important factor in brain and nerve development. Knockout mice have stubby, continuous limbs with lack of joints in the paws, along with a fatal array of other developmental defects. The gene earned its name when, in connection with studies of its role in the brain and nervous system, it was found that frog embryos injected with its mRNA grew exceptionally large heads. In the developing frog, the noggin protein also mimics the activity of the Spemann organizer, which can make dorsal tissue out of ventral tissue.
In a series of expression studies in mouse, Tucker et al. (1998) demonstrated that BMP4 activates the expression of Msx1 (142983), leading to incisor tooth development. BMP4 inhibited expression of Barx1 (603260), which marks presumptive molar teeth, and limits expression to the proximal, presumptive molar mesenchyme at embryonic day 10. Fibroblast growth factor-8 (FGF8; 600483) stimulated Barx1 expression. When BMP4 signaling in early development was inhibited by application of exogenous noggin protein, ectopic Barx1 expression resulted in transformation of tooth identity from incisor to molar.
Gazzerro et al. (1998) examined the expression of noggin and chordin in cultures of osteoblast-enriched cells from 22-day-old fetal rat calvaria. BMP2 (112261) caused a time- and dose-dependent increase in noggin mRNA and polypeptide levels. The effects of BMP2 on noggin transcripts were dependent on protein synthesis, but independent of DNA synthesis. BMP2 increased the rates of noggin transcription. BMP4, BMP6 (112266), and TGF-beta-1 (190180) increased noggin mRNA in rat calvaria cells, but basic fibroblast growth factor-2 (FGF2; 134920), platelet-derived growth factor-beta (PDGFB; 190040), and insulin-like growth factor-1 (IGF1; 147440) did not. Noggin decreased the stimulatory effects of BMPs on DNA and collagen synthesis as well as alkaline phosphatase activity in rat calvaria cells. The authors concluded that BMPs induced noggin transcription in osteoblast cells, a probable mechanism to limit BMP action in osteoblasts.
The morphogenesis of organs as diverse as lungs, teeth, and hair follicles is initiated by a downgrowth from a layer of epithelial stem cells. During follicular morphogenesis, stem cells form this bud structure by changing their polarity and cell-cell contact. Jamora et al. (2003) showed that this process is achieved through simultaneous receipt of 2 external signals: a WNT protein (WNT3A; 606359) to stabilize beta-catenin (116806), and a bone morphogenetic protein inhibitor (noggin) to produce Lef1 (153245). Beta-catenin binds to and activates Lef1 transcription complexes that appear to act uncharacteristically by downregulating the gene encoding E-cadherin (192090), an important component of polarity and intercellular adhesion. When either signal is missing, functional Lef1 complexes are not made, and E-cadherin downregulation and follicle morphogenesis are impaired. In Drosophila, E-cadherin can influence the plane of cell division and cytoskeletal dynamics. Consistent with this notion, Jamora et al. (2003) showed that forced elevation of E-cadherin levels block invagination and follicle production. Jamora et al. (2003) concluded that their findings reveal an intricate molecular program that links 2 extracellular signaling pathways to the formation of a nuclear transcription factor that acts on target genes to remodel cellular junctions and permit follicle formation.
Warren et al. (2003) demonstrated that noggin is expressed postnatally in the suture mesenchyme of patent, but not of fusing, cranial sutures, and that noggin expression is suppressed by FGF2 (134920) and syndromic FGFR signaling. Warren et al. (2003) studied the effects of Apert (S252W; 176943.0010) and Crouzon (see C342Y; 176943.0001) syndrome Fgfr2 gain-of-function mutations on noggin production in dural cell and osteoblast cultures. Both Apert and Crouzon syndrome Fgfr2 mutants markedly downregulated noggin protein production in sagittal dura mater. The Apert and Crouzon Fgfr2 constructs also downregulated Bmp4 (112262)-induced noggin expression in calvarial osteoblasts. Because both Apert and Crouzon syndrome Fgfr gain-of-function mutations promote pathologic suture fusion, Warren et al. (2003) concluded that their findings provide an important link between the murine models and the gain-of-function Fgfr mutations associated with syndromic Fgfr-mediated craniosynostoses. Warren et al. (2003) also showed that forced expression of noggin maintained posterior frontal suture patency in mice. They suggested that since ectopic noggin expression prevented the fusion of mouse posterior frontal sutures, it is possible that therapeutic noggin could be exploited to control postnatal skeletal development.
Winkler et al. (2004) found that human sclerostin (SOST; 605740) interacted directly with noggin in vitro. The sclerostin-noggin interaction neutralized the ability of either protein to bind and inhibit BMP6, permitting BMP6 mitogenic activity in a mouse osteosarcoma cell line. Immunoprecipitation of sclerostin from a rat osteosarcoma cell line indicated that endogenous rat sclerostin forms a complex with Bmp2, Bmp5 (112265), and noggin.
Proximal Symphalangism and Multiple Synostoses Syndrome 1
Gong et al. (1999) identified 5 dominant human NOG mutations in unrelated families with symphalangism (SYM1A; 185800) and a de novo mutation in a patient with unaffected parents. They also found a dominant NOG mutation in a family segregating multiple synostosis syndrome (SYNS1; 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All 7 NOG mutations altered evolutionarily conserved amino acid residues. The findings confirmed that NOG is essential for joint formation and suggested that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species. Differences between humans and mice with respect to phenotypes caused by heterozygous mutations had been observed previously with GDF5 (601146), which encodes a member of the TGF-beta superfamily. This prompted Gong et al. (1999) to determine whether similar differences result from heterozygous mutations in the TGF-beta family member antagonist NOG.
Marcelino et al. (2001) investigated the effect on the structure and function of noggin of the W217G mutation (602991.0003), which causes SYNS, and the P223L mutation (602991.0004) and the G189C (602991.0005) mutation, each of which causes SYM1. The SYNS1 mutation abolished, and the SYM1 mutations reduced, the secretion of functional noggin dimers in transiently transfected COS-7 cells. Coexpression of mutant noggin with wildtype noggin, to resemble the heterozygous state, did not interfere with wildtype noggin secretion. These data indicated that the human disease-causing mutations are hypomorphic alleles that reduce secretion of functional dimeric noggin. The authors concluded that noggin has both species-specific and joint-specific dosage-dependent roles during joint formation.
In a German father and son with multiple synostoses syndrome and overgrowth, Rudnik-Schoneborn et al. (2010) identified heterozygosity for a missense mutation (602991.0019) in the NOG gene. Rudnik-Schoneborn et al. (2010) noted that experimental evidence showed that suppression of noggin might accelerate osteogenesis (Wan et al., 2007), which could explain the accelerated growth phenotype in this family.
Tarsal-Carpal Coalition Syndrome
Dixon et al. (2001) identified 3 different missense mutations in NOG that resulted in tarsal-carpal coalition syndrome (TCC; 186570). Two of these mutations are identical to mutations previously reported to cause proximal symphalangism.
Stapes Ankylosis with Broad Thumbs and Toes
Brown et al. (2002) identified truncating mutation in the NOG gene in 2 families with autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies (184460) but without symphalangism. The first family, of Italian descent, had conductive hearing loss that was inherited as an autosomal dominant with complete penetrance. Each affected individual was thought to have had nonsyndromic otosclerosis but was found on further study to have a congenital stapes ankylosis syndrome that included hyperopia, a hemicylindrical nose, broad thumbs and big toes, and other minor skeletal anomalies. The second family was that reported by Milunsky et al. (1999).
In a 22-year-old woman of Jewish Ashkenazi origin diagnosed with Teunissen-Cremers syndrome, Hirshoren et al. (2008) identified a missense mutation in the NOG gene (602991.0012) previously found in patients with proximal symphalangism (185800) and type B2 brachydactyly (611377). Pedigree analysis revealed 7 family members with hearing loss and skeletal anomalies segregating in an autosomal dominant fashion.
Brachydactyly Type B2
In most patients with brachydactyly type B (BDB; see 113000), the characteristic terminal deficiency of fingers and toes is caused by heterozygous truncating mutations in ROR2 (602337). In a subset of ROR2-negative patients with BDB clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis (BDB2; 611377), Lehmann et al. (2007) identified 6 different missense mutations (e.g., P35A, 602991.0017) in the BMP antagonist NOG. In contrast to previously described loss-of-function mutations in NOG, which cause a range of conditions associated with abnormal joint formation but without BDB, the newly identified BDB mutations did not indicate a major loss of function, as suggested by calculation of free-binding energy of the modeled NOG-GDF5 (601146) complex and functional analysis of the micromass culture system. Rather, they presumably alter the ability of NOG to bind to BMPs and GDFs in a subtle way, thus disturbing the intricate balance for BMP signaling. The combined features observed in this phenotypic subtype of BDB argued for a functional connection between BMP and ROR2 signaling and supported 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.
Radioulnar Synostosis
In 126 patients with sporadic nonsyndromic radioulnar synostosis (RUS; 179300) and 11 families, Yang et al. (2019) sequenced the NOG and GDF5 (601146) genes, 2 major genes responsible for human multiple synostoses. They found no variants in the GDF5 gene; however, they did detect 2 missense variants in NOG (L104M and P83L). One was inherited from an affected father and the other from a mother with a minor finger deformity but no RUS. Both these variant proteins were shown to be less secretory than wildtype NOG.
The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor-beta superfamily signaling proteins, such as bone morphogenetic protein-4 (BMP4; 112262). By diffusing through extracellular matrices more efficiently than members of the TGF-beta superfamily, 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 (McMahon et al., 1998; Brunet et al., 1998).
Bachiller et al. (2000) demonstrated that at midgastrula, expression of noggin overlaps that of chordin. Noggin mutants underwent normal gastrulation and anterior central nervous system patterning, although at later stages a number of abnormalities were observed in posterior spinal cord and somites. Bachiller et al. (2000) set up intercrosses between mice compound heterozygous for noggin and chordin mutations, but no double-homozygous mutants were recovered among the neonates. Two chordin/noggin double-null embryos were found among animals dissected close to term. Both were undergoing resorption, but clearly had holoprosencephaly, with a single nasal pit, a cyclopic eye, and agnathia. These malformations, not observed in either mutant on its own, represented the weakest phenotypes found in double-mutant mice and resembled embryos lacking Sonic hedgehog (SHH; 600725). At embryonic day 12.5, double-mutant embryos were recovered with more severe phenotypes resembling aprosencephaly. In double-mutant embryos dissected at embryonic day 8.5, forebrain reduction was clearly evident. Bachiller et al. (2000) concluded that chordin and noggin are not necessary for establishing the anterior visceral endoderm but are required for subsequent elaboration of anterior pattern. Mesodermal development was also affected, indicated by the lack of shh. Bachiller et al. (2000) suggested that the BMP antagonists chordin and noggin compensate for each other during early mouse development. When both gene products are removed, antero-posterior, dorso-ventral, and left-right patterning are all affected.
Using adult Nog +/- mice with a LacZ transgene inserted at the site of the Nog deletion, Wu et al. (2003) demonstrated Nog expression in osteoblast and chondrocyte cell lines as well as bone marrow macrophages. They found that despite identical BMP levels, osteoblasts of 20-month-old C57BL/6J and 4-month-old senescence-accelerated (SAM-P6) mice had noggin expression levels that were approximately 4-fold higher than those of 4-month-old C57BL/6J and SAM-R1 (control) mice, respectively. Transgenic mice overexpressing noggin in mature osteocalcin-positive osteoblasts showed dramatic decreases in bone mineral density and bone formation rates. These results suggested that NOG, expressed in mature osteoblasts, inhibits osteoblast differentiation and bone formation. Wu et al. (2003) concluded that overproduction of NOG during biologic aging may result in impaired osteoblast formation and function and thus net bone loss.
Hwang and Wu (2008) found that the conductive hearing loss in Nog +/- mice is caused by an ectopic bone bridge located between the stapes and the posterior wall of the tympanum, which affects the normal mobility of the ossicle and likely interferes with sound conduction. Their studies suggested that ectopic bone formation is caused by a failure of the stapes and styloid process to separate completely during development. This failure of bone separation in Nog +/- mice revealed another consequence of chondrocyte hyperplasia due to unopposed BMP activities. Hwang and Wu (2008) suggested that this was the first animal model for conductive, rather than neurosensory, hearing loss.
Although there have been reports indicating that mutations in the NOG gene cause fibrodysplasia ossificans progressiva (FOP; 135100), numerous studies have refuted this association.
Lucotte et al. (1999) reported that a patient with FOP had a 42-bp heterozygous deletion in the NOG gene. To determine if NOG mutations are a general finding in FOP, Xu et al. (2000) examined 31 families with one or more FOP patients, including the patient reported by Lucotte et al. (1999). No mutations were found. Xu et al. (2000) noted that the protein-coding region of this single-exon gene is extremely GC-rich (67%), which suggests that the gene may be highly methylated and/or susceptible to secondary structure formation, conditions that interfere with the fidelity of PCR amplification and could plausibly explain the previously reported and subsequently unverifiable NOG deletion in the patient with FOP.
In 4 Spanish patients with FOP, Semonin et al. (2001) reported heterozygosity for 3 different mutations in the NOG gene. Xu et al. (2002) stated that these reported mutations in the NOG gene are PCR errors as described in their previous study (Xu et al., 2000). Warman (2002) suggested that the divergent results might arise from methodologic issues including possible phenotype error and/or the use of a nested PCR approach which increases the likelihood of PCR-induced artifacts; he proposed that photographs and radiographs of the patients with FOP and NOG mutations be published and that DNA samples from patients with putative disease-causing FOP mutations be shared with other laboratories for independent confirmation using a different methodology. Xu et al. (2002, 2000) had previously reported a patient with FOP in whom mutation in the NOG gene had been reported but not verified. Shore et al. (2006) subsequently studied this patient and identified heterozygosity for an R206H mutation (102576.0001) in the ACVR1 gene.
Using the disputed DNA sequencing techniques as previously described by Semonin et al. (2001) involving a nested approach prone to PCR-induced artifacts (Xu et al., 2000; Warman, 2002), Lucotte et al. (2007) analyzed the NOG gene in 45 unrelated patients diagnosed with FOP and reported identification of 6 additional patients with a mutation in NOG. They also identified heterozygosity for the R206H mutation in the ACRV1 gene in 23 patients, 1 of whom had previously been reported to have a 42-bp deletion in the NOG gene (Lucotte et al., 1999) and another who had been reported to carry a 'rare polymorphism' in NOG (Fontaine et al., 2005).
In their family 1 with proximal symphalangism (SYM1A; 185800), Gong et al. (1999) found a TAC (tyr)-to-TGC (cys) transition in codon 222 of the NOG gene. The family with the tyr222-to-cys mutation was the historic family originally described by Cushing (1916), updated by Strasburger et al. (1965) and found to show linkage of symphalangism with markers on 17q by Polymeropoulos et al. (1995).
In their family 4 with proximal symphalangism (SYM1A; 185800), Gong et al. (1999) found a TAC (tyr)-to-GAC (asp) transversion in codon 222 of the NOG gene.
In affected members of a large Hawaiian family with multiple synostoses (SYNS1; 186500), originally reported by Gaal et al. (1987), Gong et al. (1999) identified a heterozygous TGG (trp)-to-GGG (gly) transversion in codon 217 of the NOG gene. Affected individuals demonstrated cardinal features of the syndrome, including a broad, tubular-shaped nose, otosclerotic deafness, and multiple progressive joint fusions commencing in the hand. In addition, the cervical vertebral fusions commenced in early childhood and ultimately produced significant limitations of neck flexion and extension in this family.
In their family 3 with proximal symphalangism (SYM1A; 185800), Gong et al. (1999) found a CCC (pro)-to-CTC (leu) transition in codon 223 of the NOG gene.
In their family 5 with proximal symphalangism (SYM1A; 185800), Gong et al. (1999) found a GGC (gly)-to-TGC (cys) change in codon 189 of the NOG gene.
In affected members of the family with tarsal-carpal coalition syndrome (TCC; 186570) reported by Drawbert et al. (1985), Dixon et al. (2001) identified a G-to-T transversion in the NOG gene resulting in an arg204-to-leu (R204L) substitution.
In affected members of a family with tarsal-carpal coalition syndrome (TCC; 186570), Dixon et al. (2001) identified a C-to-G transversion in the NOG gene resulting in a pro-to-arg substitution at codon 35 (P35R). This mutation had previously been reported in a sporadic case of proximal symphalangism (SYM1A; 185800) by Gong et al. (1999).
In affected members of a family with tarsal-carpal coalition syndrome (TCC; 186570), Dixon et al. (2001) identified an A-to-G transition in the NOG gene resulting in a tyrosine-to-cysteine substitution at codon 222 (Y222C). This mutation was previously identified by Gong et al. (1999) in a large SYM1 kindred (SYM1A; 185800).
Takahashi et al. (2001) found a mutation in the NOG gene, cys184 to tyr (C184Y), in a sporadic case of proximal symphalangism (SYM1A; 185800). The parents of the patient did not show the mutation, indicating that it was de novo.
In a mother and 2 sons with proximal symphalangism (SYM1A; 185800), Takahashi et al. (2001) found a leu129-to-ter nonsense mutation in the NOG gene. The mutation was present in heterozygous state. The 7-year-old propositus had unilateral conductive deafness.
In affected members of a family with multiple synostosis syndrome (SYNS1; 186500), Takahashi et al. (2001) found a 1-bp deletion, 58delC, in the NOG gene, causing a frameshift. The propositus of this family had been reported by Higashi and Inoue (1983). The affected patients showed unusual facial appearance, nasal abnormality, conductive deafness, pectus carinatum, and proximal symphalangism. The nasal tip was peculiarly widened and flat.
Mangino et al. (2002) studied an Italian family in which a father and son had bilateral symphalangism (SYM1A; 185800) and found a novel pro35-to-ser (P35S) mutation in the NOG gene that originated in the father from a 914C-T transition. A different mutation in the same codon (pro35 to arg; 602991.0007) had been previously described. Different NOG homologs show conservation of codon 35, which may play an important role in NOG gene function.
In 2 unrelated individuals, Lehmann et al. (2007) observed heterozygosity for the P35S mutation as the cause of brachydactyly type B2 (611377).
In a 22-year-old woman of Jewish Ashkenazi origin who had bilateral stapes ankylosis, hyperopia, broad thumbs, symphalangism, cutaneous syndactyly, hypoplastic nails, and brachydactyly, who was diagnosed as having Teunissen-Cremers syndrome (184460), Hirshoren et al. (2008) identified heterozygosity for the P35S mutation in the NOG gene. Her father had a more severe phenotype, with hypoplastic nails and brachytelephalangia of multiple fingers and toes. Pedigree analysis revealed 7 family members with hearing loss and skeletal anomalies segregating in an autosomal dominant fashion. Commenting on the bilateral lens opacities present in the proband, which had not previously been reported in Teunissen-Cremers or other NOG syndromes, Hirshoren et al. (2008) noted that the noggin/BMP pathway had been shown to play an important role in the chick and mouse ocular development (see Trousse et al. (2001) and Furuta and Hogan (1998), respectively).
Brown et al. (2002) ascertained a family of Italian descent that had conductive hearing loss inherited as an autosomal dominant trait with complete penetrance. Each affected individual was thought to have had nonsyndromic otosclerosis, but was found upon further study to have stapes ankylosis syndrome without symphalangism (184460). Conductive hearing loss was documented at the age of 4 years or less and remained stable through subsequent years. All but 1 affected family member had hyperopia, and corrective lenses were required at ages varying from 2 to 22 years. Symmetrically short distal thumb phalanges were noted in each family member with no evidence of symphalangism. The affected members were found to be heterozygous for a 328C-T transition in the NOG cDNA, resulting in a gln110-to-ter (Q110X) mutation predicted to truncate the latter half of the protein.
In the family with autosomal dominant stapes ankylosis with broad thumbs and toes (184460) reported by Milunsky et al. (1999), Brown et al. (2002) found a 1-bp insertion in the NOG cDNA (252insC) causing a frameshift predicted to result in 96 novel amino acids before premature termination.
Dawson et al. (2006) described heterozygosity for a trp205-to-stop (W205X) missense mutation in an individual with multiple synostoses syndrome (SYNS1; 186500).
In affected members of a family segregating multiple synostoses syndrome (SYNS1; 186500), van den Ende et al. (2005) identified heterozygosity for a 615G-C transversion in the NOG gene, leading to a trp205-to-cys substitution.
In affected members of a family with brachydactyly type B2 (BDB2; 611377), Lehmann et al. (2007) detected a heterozygous 103C-G transversion in the NOG gene that resulted in a pro35-to-ala (P35A) substitution.
In a patient from North America with brachydactyly type B2 (BDB2; 611377), Lehmann et al. (2007) detected a heterozygous de novo 499C-G transversion in the NOG gene that resulted in an arg167-to-gly (R167G) substitution in the protein.
In a German father and son with multiple synostoses syndrome (SYNS1; 186500), Rudnik-Schoneborn et al. (2010) identified heterozygosity for a 696G-C transversion in the NOG gene, resulting in a cys232-to-trp (C232W) substitution. The mutation was not found in 86 German control individuals. In contrast to the typical presentation, the height of the 10-year-old son was above the 97th centile from the age of 3.5 years, and he had markers of an activated bone metabolism, with elevated phosphate levels and bone-derived alkaline phosphatase activity. His father, who had never been under medical supervision, was reported to have been one of the tallest boys in childhood and youth until age 15 years, when growth velocity slowed; his adult height was in the 75th centile (185 cm). Rudnik-Schoneborn et al. (2010) noted that experimental evidence showed that suppression of noggin might accelerate osteogenesis (Wan et al., 2007), which could explain the accelerated growth phenotype in this family.
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