Alternative titles; symbols
HGNC Approved Gene Symbol: GDF5
SNOMEDCT: 389167007, 715474004, 720569006, 77542002;
Cytogenetic location: 20q11.22 Genomic coordinates (GRCh38): 20:35,433,347-35,454,749 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q11.22 | ?Acromesomelic dysplasia 2C, Hunter-Thompson type | 201250 | Autosomal recessive | 3 |
| {Osteoarthritis-5} | 612400 | 3 | ||
| Acromesomelic dysplasia 2A | 200700 | Autosomal recessive | 3 | |
| Acromesomelic dysplasia 2B | 228900 | Autosomal recessive | 3 | |
| Brachydactyly, type A1, C | 615072 | Autosomal dominant; Autosomal recessive | 3 | |
| Brachydactyly, type A2 | 112600 | Autosomal dominant | 3 | |
| Brachydactyly, type C | 113100 | Autosomal dominant | 3 | |
| Multiple synostoses syndrome 2 | 610017 | Autosomal dominant | 3 | |
| Symphalangism, proximal, 1B | 615298 | Autosomal dominant | 3 |
The TGF-beta (TGFB; 191080) superfamily comprises a number of functionally diverse growth factors/signaling molecules that elicit their response upon binding to serine-threonine kinase receptors. Storm et al. (1994) identified 3 novel members of the TGFB superfamily in mice, designated Gdf5, Gdf6 (601147), and Gdf7 (604651), which are closely related to the bone morphogenetic proteins (see BMP9, 605120). Each of the deduced proteins contains a putative polybasic proteolytic processing site followed by a C-terminal region containing 7 conserved cysteine residues. High sequence identity among the Gdf proteins suggested that they comprise a novel TGFB subfamily.
By degenerate PCR and 3-prime RACE of a human embryo cDNA library, followed by screening a fibroblast cDNA library, Hotten et al. (1994) cloned GDF5. The deduced 501-amino acid protein contains a potential N-glycosylation site in the N-terminal propeptide region and a putative polybasic processing site (RRKKRR) in the C terminus. Upon processing, the mature GDF5 protein contains 120 amino acids and has a calculated molecular mass of 13.6 kD. The mouse and human GDF5 precursor proteins share 91% identity, and the mature proteins differ in only 1 amino acid. The putative N-glycosylation site in the propeptide and all 10 cysteines are conserved. Following infection with recombinant vaccinia virus carrying GDF5 cDNA, osteosarcoma cells expressed GDF5 at an apparent molecular mass of about 15 kD under reducing conditions. GDF5 showed an apparent molecular mass of about 25 kD under nonreducing conditions, indicating that GDF5 is expressed as a dimer. An apparent 70-kD protein, likely the uncleaved precursor protein, was also found under reducing conditions.
Chang et al. (1994) also isolated and characterized human GDF5, which they designated CDMP1, as well as human GDF6 (CDMP2). GDF6 is predominantly expressed at sites of skeletal morphogenesis. Expression is normally restricted to the primordial cartilage of appendicular skeleton, with little expression in the axial skeleton such as vertebrae and ribs.
Storm and Kingsley (1996) found that Gdf5 was expressed in a pattern of transverse stripes within many skeletal precursors in developing mouse limb. The number, location, and time of appearance of these stripes corresponded to sites where joints would later form between skeletal elements.
Hotten et al. (1994) determined that the GDF5 gene contains 2 exons.
In the mouse, the brachypodism (bp) mutant was mapped to linkage group V (Runner, 1959), which is known to be located on the distal region of mouse chromosome 2. Storm et al. (1994) mapped the mouse Gdf5 gene to the same region of chromosome 2, between the agouti and Src loci. This region shares syntenic homology with human chromosome 20q11.2. Lin et al. (1996) mapped the GDF5 gene to 20q11.2, where it is tightly linked to D20S191 and D20S195.
CD14 (158120) and lipopolysaccharide (LPS)-binding protein (LBP; 151990) are major receptors for LPS; however, binding analyses and TNF production assays have suggested the presence of additional cell surface receptors, designated LPS-associated proteins (LAPs), that are distinct from CD14, LBP, and the Toll-like receptors (see TLR4; 603030). Using affinity chromatography, peptide mass fingerprinting, and fluorescence resonance energy transfer, Triantafilou et al. (2001) identified 4 diverse proteins, heat shock cognate protein (HSPA8; 600816), HSP90A (HSPCA; 140571), chemokine receptor CXCR4 (162643), and GDF5, on monocytes that form an activation cluster after LPS ligation and are involved in LPS signal transduction. Antibody inhibition analysis suggested that disruption of cluster formation abrogates TNF release. Triantafilou et al. (2001) proposed that heat shock proteins, which are highly conserved from bacteria to eukaryotic cells, are remnants of an ancient system of antigen presentation and defense against microbial pathogens.
Settle et al. (2003) found that mouse Gdf5, Gdf6, and Gdf7 (604651) are required for normal formation of bones and joints in the limbs, skull, and axial skeleton. All were expressed in stripes across developing skeletal condensations before the precursors had separated into obviously distinct cartilage elements and joints. The expression of Gdf5 and Gdf6 was much more restricted than that of Gdf7.
Capellini et al. (2017) identified an enhancer element, which they called GROW1, within the 3-prime region of the GDF5 gene. This element has 2 regions of evolutionary conservation: one conserved through amniotes (GROW1A), and the other conserved in placental mammals (GROW1B). The mouse ortholog of GROW1 increased the length of all metapodial and major long bones. Capellini et al. (2017) identified a G-to-A SNP (rs4911178) within a highly conserved region of GROW1B, where G is perfectly conserved in placental mammals. The A allele, which occurs at high frequency in Eurasian populations, alters a predicted binding site for PITX1 (602149). Loss of PITX1 binding significantly decreased expression of a GDF5 reporter in both cultured human growth-plate chondrocytes and in long bones of transgenic mice.
Thomas et al. (1996) stated that CDMP1 is synthesized in a 'pro' form that subsequently dimerizes by a single interchain disulfide bond. A mature biologically active region is formed following cleavage at a characteristic arg-X-X-arg site. The overall structure of the mature protein is determined by the invariable spacing of 7 cysteine residues, 1 of which is involved in the formation of the interchain disulfide bond. The importance of the cysteine residues in determining the structure and ultimate function of TGF-beta superfamily members has been inferred from x-ray and NMR studies and demonstrated by site-directed mutagenesis. Replacement of any 1 of the 7 conserved cysteine residues of TGF-beta-1 by a serine produces a dramatic reduction of activity. The mutation in Hunter-Thompson type chondrodysplasia occurs in the mature region at position 1475, 11 amino acids after the third cysteine, disrupting the highly conserved 7 cysteine pattern, and results in a mature protein where only the first 62 out of 120 amino acids are in-frame. The 43 out-of-frame amino acids share no identity to the normal protein. The authors speculated that differences observed between Hunter-Thompson type chondrodysplasia and the brachypodism (bp) mouse phenotype (caused by mutation in the Gdf5 gene) may be due to genetic background, differences between human and mouse skeletal development, or interspecies variation in expression patterns of other compensatory gene products.
Acromesomelic Dysplasia 2A
Thomas et al. (1997) showed that a cys400-to-tyr mutation (C400Y; 601146.0003) in the CDMP1 gene resulted in Grebe chondrodysplasia (AMD2A; 200700). They found that the mutant protein is not secreted and is inactive in vitro. It produced a dominant-negative effect by preventing the secretion of other, related bone morphogenetic proteins (BMPs). This appeared to occur through the formation of heterodimers. The mutation and its proposed mechanism of action provided the first human genetic indication that composite expression patterns of different BMPs dictate limb and digit morphogenesis. The role of a dominant-negative mutation in a recessive disorder was illustrated.
Acromesomelic Dysplasia 2B
Acromesomelic dysplasia-2B (AMD2B; 228900), also known as Du Pan syndrome, is an autosomal recessive trait characterized by either reductions or absence of bones in the limbs and appendicular bone dysmorphogenesis with unaffected axial bones. Because of similarities to the Hunter-Thompson (AMD2C) and Grebe (AMD2A) types of acromesomelic dysplasia, Faiyaz-Ul-Haque et al. (2002) examined genomic DNA from a Pakistani family with Du Pan syndrome for mutations in the CDMP1 gene and identified homozygosity for an L441P mutation (601146.0005).
Acromesomelic Dysplasia 2C
Thomas et al. (1996) demonstrated a mutation in the CDMP1 gene (601146.0001) in acromesomelic dysplasia of the Hunter-Thompson type (AMD2C; 201250). This disorder is phenotypically similar to murine brachypodism (bp), a recessive trait due to mutations in Gdf5 (Storm et al., 1994).
Brachydactyly Type C
Polinkovsky et al. (1997) identified heterozygosity for an arg301-to-ter (R301X; 601146.0002) mutation in the CDMP1 in autosomal dominant brachydactyly type C (BDC; 113100). Everman et al. (2002) showed that a family whose type C brachydactyly was initially thought to map to chromosome 12 actually had a 23-bp insertion mutation in the CDMP1 gene (601146.0006). They reported heterozygous CDMP1 mutations in 9 additional probands/families with brachydactyly type C and presented in vitro expression data suggesting functional haploinsufficiency as the mechanism of mutational effect that caused brachydactyly type C.
Schwabe et al. (2004) described a large consanguineous Turkish kindred with a semidominant form of brachydactyly type C in which affected members were homozygous for a missense mutation (601146.0008) and heterozygous carriers of the mutation had mild shortening of metacarpals 4 and 5.
Yang et al. (2008) analyzed the GDF5 gene in 2 Han Chinese families, 1 with brachydactyly type C and 1 with proximal symphalangism, and identified heterozygosity for a Y487X mutation (601146.0016) and an L373R mutation (601146.0017), respectively. Mature GDF5 protein was detected in supernatant derived from L373R-transfected cells, but not in supernatant from Y487X-transfected cells, indicating that the 2 mutations led to different fates of the mutant GDF5 proteins, thereby producing distinct limb phenotypes.
Brachydactyly Type A2
In a family with type A2 brachydactyly (BDA2; 112600) and another with proximal symphalangism (SYM1B; 615298), Seemann et al. (2005) identified missense mutations in the GDF5 gene (L441P and R438L, 601146.0011, respectively). Functional studies revealed loss of binding to the BMPR1A (601299) and BMPR1B (603248) ectodomains for the L441P mutant, whereas the R438L mutant had normal binding to BMPR1B and increased binding to BMPR1A; binding to NOG (602991) was normal for both. Seemann et al. (2005) concluded that the brachydactyly A2 phenotype is caused by inhibition of ligand-receptor interaction, whereas the symphalangism phenotype is caused by a loss of receptor-binding specificity, resulting in a gain of function due to the acquisition of BMP2-like properties.
In the original BDA2 family reported by Mohr and Wriedt (1919), Kjaer et al. (2006) identified heterozygosity for the L441P mutation in the GDF5 gene.
In 14 affected individuals from a 6-generation family with BDA2 in whom no mutations in the BMPR1B gene were identified, Ploger et al. (2008) identified heterozygosity for a missense mutation in the GDF5 gene (R380Q; 601146.0021). Functional analysis demonstrated that the R380Q mutation results in reduced GDF5 function caused by diminished proteolytic cleavage, which is a precondition to generate biologically active GDF5.
Brachydactyly, Type A1, C
In 3 affected sibs from a consanguineous French Canadian family with type A1 brachydactyly mapping to chromosome 20q11 (BDA1C; 615072), Byrnes et al. (2010) identified homozygosity for a missense mutation in the candidate gene GDF5 (R399C; 601146.0020). The proband's son, who had a milder phenotype, was heterozygous for the R399C mutation, consistent with a semidominant pattern of inheritance.
Multiple Synostoses Syndrome 2
Multiple synostoses syndrome (SYNS1; 186500) is characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism. Heterozygosity for functional null mutations in the noggin gene (NOG; 602991) can be responsible for the disorder. Akarsu et al. (1999) described a large Iranian family with a multiple synostosis syndrome, which they designated SYNS2 (610017), mapping to chromosome 20q11.2. They found a heterozygous missense mutation in the GDF5 gene (601146.0014) as the cause of the disorder.
In a family with multiple synostoses syndrome in which linkage to the noggin locus had been excluded, Dawson et al. (2006) found that polymorphic markers flanking the GDF5 locus segregated with the disorder. Sequence analysis demonstrated that affected individuals in the family were heterozygous for a novel missense mutation that predicted an R438L substitution in the GDF5 protein (601146.0011). Unlike mutations that lead to haploinsufficiency for GDF5 and produce brachydactyly C, the protein encoded by the multiple synostoses syndrome allele was secreted as a mature GDF5 dimer.
Proximal Symphalangism
In affected members of 2 large 5-generation Chinese families with SYM1B (615298), Wang et al. (2006) identified heterozygosity for a missense mutation in the GDF5 gene (E491K; 601146.0014).
In a Han Chinese family with proximal symphalangism, Yang et al. (2008) found a L373R mutation in the GDF5 gene (601146.0017). Mature GDF5 protein was detected in supernatant derived from L373R-transfected cells.
In a family with proximal symphalangism, Seemann et al. (2005) identified a R438L mutation in the GDF5 gene (601146.0011). Functional studies revealed that the R438L mutant had normal binding to BMPR1B (603248) and increased binding to BMPR1A (601229), with normal binding to NOG (602991). Seemann et al. (2005) concluded that the symphalangism phenotype is caused by a loss of receptor-binding specificity, resulting in a gain of function due to the acquisition of BMP2-like properties. These authors also detected and functionally characterized a missense mutation in a family with type A2 brachydactyly (see 601146.0005).
Osteoarthritis Susceptibility 5
Osteoarthritis (see 165720), characterized by degeneration of articular cartilage, is the most common form of human arthritis and a major concern for aging societies worldwide. Miyamoto et al. (2007) found that a SNP in the 5-prime untranslated region (UTR) of the GDF5 gene (601146.0015) is associated with osteoarthritis in Asian populations. This SNP, located in the GDF5 core promoter, exerts allelic differences on transcriptional activity in chondrogenic cells, with the susceptibility allele showing reduced activity. The findings implicated GDF5 as a susceptibility gene for osteoarthritis and suggested that decreased GDF5 expression is involved in the pathogenesis of osteoarthritis. Miyamoto et al. (2007) cited preliminary evidence that mice carrying a dominant/negative mutation in Gdf5 show osteoarthritic phenotypes. The authors concluded that their findings pointed to an important role for GDF5 in articular cartilage homeostasis and indicated that decreased GDF5 expression may lead to susceptibility to osteoarthritis. Therefore, increased GDF5 expression or enhancement of its downstream signal could help to prevent osteoarthritis.
To identify rare variants in GDF5 that could influence OA susceptibility either by acting as independent risk factors or by modulating the influence of rs143383 (601146.0015), Dodd et al. (2013) performed deep sequencing of GDF5 and identified a C-to-A transversion in the proximal promoter, 41 basepairs upstream of the transcription start site. This promoter variant was predicted to affect transcription factor binding and may therefore highlight a regulatory site that could be exploited to manipulate GDF5 expression and alleviate the detrimental effect mediated by the T allele of rs143383. Using reporter constructs, Dodd et al. (2013) demonstrated that the transversion leads to increased gene expression to such a degree that the A allele is able to compensate for the reduced expression mediated by the T allele of rs143383. Dodd et al. (2013) then used electrophoretic mobility shift assays to identify YY1 (600013) as a trans-acting factor that differentially binds to the alleles of the -41-bp variant, with more avid binding to the A allele. Knockdown of YY1 led to a significant reduction in GDF5 expression, supporting YY1 as a GDF5 activator.
Stature as a Quantitative Trait
See STQTL14 (612228) for a discussion of genetic variation influencing height associated with the GDF5-UQCC (611797) locus.
Storm et al. (1994) identified mutations in the Gdf5 gene as the cause of the mouse brachypodism (bp) phenotype; bp null mutations alter bone lengths and the number of segments in the digits of all 4 limbs, but do not affect ear, sternum, rib, or vertebral morphology.
Storm and Kingsley (1996) found that null mutations in Gdf5 disrupted formation of more than 30% of synovial joints in mouse limb, leading to complete or partial fusions between skeletal elements and changes in the pattern of repeating structures in the digits, wrists, and ankles. Mice carrying a null mutation in both Gdf5 and Bmp5 (112265) showed additional abnormalities not observed in either of the single mutants, including disruption of sternebrae within the sternum and abnormal formation of fibrocartilaginous joints between sternebrae and ribs.
Tsumaki et al. (1999) generated transgenic mice expressing recombinant CDMP1. These mice died before or just after birth and exhibited chondrodysplasia with expanded primordial cartilage, which consisted of an enlarged hypertrophic zone and a reduced proliferating chondrocyte zone, not only in the limbs but also in the axial skeleton. Histologically, CDMP1 increased the number of chondroprogenitor cells and accelerated chondrocyte differentiation to hypertrophy. Moreover, ectopic expression of CDMP1 in the notochord before onset of chondrogenesis inhibited mesenchymal cell condensation around the notochord, which led to failure of vertebral body formation.
Settle et al. (2003) found that Gdf5/Gdf6 double-mutant mice survived to birth in normal mendelian ratios, but only a small percentage survived to adulthood. The double-mutant mice had skeletal defects not seen in either Gdf5 or Gdf6 single mutants. Many limb bones were severely reduced or absent, several limb joints failed to form, and the vertebral column of 2 of 7 mice showed severe scoliosis.
In a mutant line of mice (M100451) exhibiting a brachypodism phenotype, Masuya et al. (2007) identified a W408R substitution in a highly conserved region of the active signaling domain of the Gdf5 protein. The mutation was semidominant, with heterozygotes showing brachypodism and ankylosis, whereas homozygotes showed much more severe brachypodism, ankylosis of the knee joint, and malformation of the elbow joint with early-onset osteoarthritis. Functional studies revealed that W408R Gdf5 protein is secreted and dimerizes normally, but inhibits the function of wildtype Gdf5 protein in a dominant-negative fashion. Masuya et al. (2007) concluded that Gdf5 plays a critical role in joint formation and development of osteoarthritis, and that M100451 mouse should serve as a good model for osteoarthritis.
Using mice with skeletal muscle-specific knockout or knockdown of BMP signaling molecules, Sartori et al. (2013) found that BMP signaling, acting via Smad1 (601595), Smad5 (603110), and Smad8 (SMAD9; 603295) (Smad1/5/8) and Smad4 (600993), regulated muscle mass. Inhibition of BMP signaling caused muscle atrophy, abolished the hypertrophic phenotype of myostatin (MSTN; 601788)-deficient mice, and exacerbated the muscle-wasting effects of denervation and fasting. Bmp14 was required to prevent excessive muscle loss following denervation. The BMP-Smad1/5/8-Smad4 pathway negatively regulated Fbxo30 (609101), a ubiquitin ligase required for muscle loss. Inhibition of Fbxo30 protected denervated muscle from atrophy and blunted atrophy in Smad4-deficient muscle. Sartori et al. (2013) concluded that BMP signaling is the dominant pathway controlling muscle mass and that the hypertrophic phenotype caused by myostatin inhibition results from unrestrained BMP signaling.
Using CRISPR-Cas9 editing, Capellini et al. (2017) deleted the GROW1 enhancer from the 3-prime region of the mouse Gdf5 gene. Mutant mice were born at the expected mendelian ratio and were viable and fertile. However, loss of GROW1 significantly reduced expression of Gdf5 in bone and reduced the lengths of the femoral neck, femur, and tibia by approximately 7.5%
In a family described by Langer et al. (1989) from the Choco District of Colombia affected with the Hunter-Thompson type of chondrodysplasia (AMD2C; 201250), Thomas et al. (1996) demonstrated that affected members were homozygous for a 22-bp tandem duplication frameshift mutation in the mature region of the CDMP1 protein. Hunter-Thompson-type chondrodysplasia and mouse 'bp' are typified by abnormalities restricted to the limbs and the severity of the long bone shortening progresses in a proximal to distal direction. The hands and feet are most severely affected but the distal phalanges are relatively normal.
In a family with brachydactyly type C (BDC; 113100) previously reported by Robin et al. (1997), Polinkovsky et al. (1997) showed that affected members were heterozygous for a C-to-T transition at nucleotide 901 of the mRNA coding sequence of the CDMP1 gene, converting the codon specifying arginine at amino acid residue 301 to a stop codon. Additional CDMP1 mutations were also found in 5 unrelated persons with presumed type C brachydactyly. The family studied by Robin et al. (1997) had 12 affected individuals across 5 generations; shortening of the second, third, and fifth middle phalanges was the principal finding.
Thomas et al. (1997) identified homozygosity for a G-to-A transition at nucleotide 1199 in the CDMP1 gene, predicted to result in a tyrosine for cysteine substitution at amino acid 400 in the mature region of CDMP-1 in a family with Grebe chondrodysplasia (AMD2A; 200700).
Thomas et al. (1997) found that heterozygotes for the C400Y mutation had phenotypes resembling brachydactyly types A1 (112500), A4 (112800), or C (BDC; 113100).
Faiyaz-Ul-Haque et al. (2002) described a family in which 7 males and 6 females inherited Grebe chondrodysplasia (AMD2A; 200700) in an autosomal recessive pedigree pattern. Whereas the carrier parents did not exhibit any apparent skeletal abnormalities, all affected individuals had a similar phenotype with unaffected axial and craniofacial bones. Faiyaz-Ul-Haque et al. (2002) discovered an insertion of a C at nucleotide 297 of the coding sequence in affected individuals. This insertion produced a shift in the reading frame at amino acid residue 99, causing premature termination of the polypeptide 6 amino acids downstream.
Acromesomelic Dysplasia 2B
In a consanguineous Pakistani family with Du Pan syndrome (AMD2B; 228900), Faiyaz-Ul-Haque et al. (2002) found that affected individuals were homozygous for a 1322T-C transition in the coding region of the CDMP1 gene, predicted to result in a leu441-to-pro (L441P) substitution.
Brachydactyly, Type A2
In a large Norwegian pedigree with brachydactyly type 2A (112600), Seemann et al. (2005) identified heterozygosity for the L441P mutation, which is located in the receptor interaction site. Functional studies in limb bud micromass culture and ATDC5 and C2C12 cells showed that the L441P mutant is almost inactive; biosensor interaction analysis revealed loss of binding to BMPR1A (601229) and BMPR1B (603248) ectodomains.
In 22 of 37 living members of the Norwegian family of Danish descent with brachydactyly type A2 originally described by Mohr and Wriedt (1919), Kjaer et al. (2006) identified heterozygosity for the L441P mutation in the GDF5 gene. Three of the mutation carriers were clinically unaffected. The mutation was also identified in a Danish individual with a similar phenotype.
Everman et al. (2002) demonstrated that the affected members of the family with brachydactyly type C (BDC; 113100) studied by Haws (1963) had a 23-bp insertion at position 811 of the GDF5 gene as the cause of their anomaly.
In 4 sibs with Grebe acromesomelic dysplasia (AMD2A; 200700) from an Omani family, Al-Yahyaee et al. (2003) identified 2 mutations in the GDF5 gene: a silent 1137A-G transition encoding lysine and a 1-bp deletion, 1144delG, predicting a frameshift resulting in loss of the biologically active C terminus of the protein. The affected sibs were homozygous for the 1144delG mutation and each parent was heterozygous. The affected sibs had normal axial skeletons, severely shortened and deformed limbs with severity increasing in a proximodistal gradient, and subluxated joints. The humeri and femora were hypoplastic with distal malformations. The radii/ulnae were shortened and deformed whereas carpal bones were invariably rudimentary or absent. The tibiae appeared rudimentary; fibulae were absent in 2 children, and some tarsal and metatarsal bones were absent. Only distal phalanges were present. The father and mother had short first metacarpal and middle phalanx of the fifth finger and hallux valgus, respectively.
In a large consanguineous Turkish kindred with brachydactyly type C (BDC; 113100), Schwabe et al. (2004) identified a homozygous 517A-G transition in the GDF5 gene, predicting a met173-to-val substitution within a highly conserved 7-amino acid region of the CDMP1 prodomain. Homozygous offspring of consanguineous unions exhibited features of BDC consisting of brachymesophalangy and hyperphalangy of the second, third, and fifth fingers with some phenotypic variability. Schwabe et al. (2004) noted that all heterozygous mutation carriers showed mild shortening of metacarpals 4 and 5, suggesting a semidominant pattern of inheritance.
In 8 members of 3 unrelated families with type C brachydactyly (BDC; 113100), Savarirayan et al. (2003) identified a heterozygous 1-bp insertion in the GDF5 gene, 206insG, resulting in a frameshift and premature termination 25 amino acids downstream. The change was not detected in 100 control alleles. Axial skeleton involvement was found in 4 carriers with clinical and radiographic evidence of premature vertebral endplate disease, and associated spondylolysis and spondylolisthesis were also found in 3 of these 4. Two carriers had severe bilateral vertical talus, and 1 had developmental hip dysplasia. Four members from the 3 families were also heterozygous for the 1-bp insertion, but had normal hands and feet. Two of these 4 nonpenetrant cases had what had been regarded as constitutional short stature.
In affected members of a family with proximal symphalangism (SYM1B; 615298), Seemann et al. (2005) identified a 1632G-T transversion in the GDF5 gene, resulting in an arg438-to-leu (R438L) substitution. Functional studies in limb bud micromass culture and ATDC5 and C2C12 cells showed increased biologic activity when compared to wildtype GDF5; biosensor interaction analysis revealed normal binding to BMPR1B ectodomain but increased binding to that of BMPR1A.
In a kindred with multiple synostoses syndrome (SYNS2; 610017) in which sequence analysis as well as linkage analysis excluded involvement of the noggin locus (NOG; 602991), Dawson et al. (2006) found that polymorphic markers flanking the GDF5 locus cosegregated with the disease. Sequence analysis demonstrated that affected individuals in the family were heterozygous for a G-to-T transversion in the GDF5 gene that predicted an arg438-to-leu (R438L) substitution in the GDF5 protein. (Dawson et al. (2006) referred to the nucleotide substitution as 1313G-T.) Unlike mutations that lead to haploinsufficiency for GDF5 and produce brachydactyly C (113100), the protein encoded by the multiple synostoses syndrome allele was secreted as a mature GDF5 dimer.
In a Polish mother and daughter with Du Pan syndrome (AMD2B; 228900), Szczaluba et al. (2005) identified heterozygosity for 3 mutations on the same allele of the GDF5 gene. The mutations included a 3-bp deletion (1309delTTG), resulting in a deletion of leu437, a 1315T-A transversion, resulting in a ser439-to-thr (S439T) substitution, and a 1319A-T transversion, resulting in a his440-to-leu (H440L) substitution. All of the mutations occurred in the active domain of the protein. Szczaluba et al. (2005) postulated that the 3 mutations had a synergistic cis-acting dominant-negative effect on gene expression, resulting in autosomal dominant inheritance of the disorder in this family.
In a large Iranian family with tarsal-carpal coalition, humeroradial synostosis, brachydactyly, and proximal symphalangism inherited in an autosomal dominant pattern (SYNS2; 610017), Akarsu et al. (1999) found a heterozygous ser475-to-asn (S475N) mutation in GDF5 that segregated with the phenotype in 39 affected and 27 unaffected individuals. Ser475 lies in a highly conserved region of the protein.
In affected members of 2 large 5-generation Chinese families with proximal symphalangism-1B (SYM1B; 615298), Wang et al. (2006) identified heterozygosity for a 1471G-A transition in exon 2 of the GDF5 gene, resulting in a glu491-to-lys (E491K) substitution in the TGF-beta (190180) domain. SSCP analysis demonstrated that the E491K mutation cosegregated with all affected individuals in both families, and the mutation was not found in 200 healthy controls. Although there was inter- and intrafamily variation of clinical features in affected individuals, penetrance was complete.
Miyamoto et al. (2007) found significant association (p = 1.8 x 10(-13)) between a SNP in the 5-prime untranslated region (UTR) of GDF5, +104T/C (rs143383), and hip osteoarthritis (OS5; 612400) in 2 independent Japanese populations. This association was replicated for knee osteoarthritis in Japanese (p = 0.0021) and Han Chinese (p = 0.00028) populations. This SNP, located in the GDF5 core promoter, exerts allelic differences on transcriptional activity in chondrogenic cells, with the susceptibility allele (T) showing reduced activity. The findings implicated GDF5 as a susceptibility gene for osteoarthritis and suggested that decreased GDF5 expression is involved in the pathogenesis of osteoarthritis.
In affected members of a large 4-generation Han Chinese family segregating autosomal dominant brachydactyly type C (BDC; 113100), Yang et al. (2008) identified heterozygosity for a 1461T-G transversion in the GDF5 gene, resulting in a tyr487-to-ter (Y487X) substitution predicted to truncate the GDF5 precursor polypeptide by 15 amino acids, deleting 2 of 7 C-terminal cysteine residues. The mutation was not detected in an unaffected family member or in 50 controls.
In the proband of a 4-generation Han Chinese family with autosomal dominant proximal symphalangism (SYM1B; 615298), who was negative for mutation in the NOG gene (602991), Yang et al. (2008) identified heterozygosity for a 1118T-G transversion in the GDF5 gene, resulting in a leu373-to-arg (L373R) substitution at a highly conserved residue in the GDF5 prodomain. The mutation was not detected in 3 unaffected family members or in 50 controls.
In a 20-month-old boy with Du Pan syndrome (AMD2B; 228900), Douzgou et al. (2008) identified compound heterozygosity for 2 mutations in the GDF5 gene: a 1133G-A transition resulting in an arg378-to-gln (R378Q) substitution inherited from the father, and a 1306C-A transversion resulting in a pro436-to-thr (P436T; 601146.0019) substitution inherited from the mother. The R378Q substitution is located at the end of the prodomain within the recognition motif at the processing site of GDF5 where the precursor protein is cleaved and was predicted to result in at least partial loss of function. The P436T substitution is located within the mature domain of GDF5 and was predicted to interfere with binding to BMPR1B (603248). The patient's mother was unaffected, whereas the father had very mild radiographic features of brachymesophalangy of the hand digits.
For discussion of the pro436-to-thr (P436T) mutation in the GDF5 gene that was found in compound heterozygous state in a patient with Du Pan syndrome (AMD2B; 228900) by Douzgou et al. (2008), see 601146.0018.
In 3 affected sibs from a consanguineous French Canadian family with type A1 brachydactyly (BDA1C; 615072), Byrnes et al. (2010) identified homozygosity for a 1195C-T transition in the GDF5 gene, resulting in an arg399-to-cys (R399C) substitution at a highly conserved residue in the mature active region. The mutation was not found in 2 unaffected sisters or in 400 control chromosomes; the proband's son, who was mildly affected, carried the R399C mutation in heterozygosity, consistent with a semidominant pattern of inheritance.
In 14 affected individuals from a 6-generation family with type A2 brachydactyly (BDA2; 112600), Ploger et al. (2008) identified heterozygosity for a 1139G-A transition in the GDF5 gene, resulting in an arg380-to-gln (R380Q) substitution at the P2 position of the subtilisin-like proprotein convertase processing site. The mutation was not found in unaffected family members. Analysis of the R380Q mutant in chicken micromass cultures demonstrated secretion of the mutant but showed a severe reduction in biologic activity. Western blot analyses showed that the mutation interferes with GDF5 processing, and studies in E. coli confirmed that unprocessed proGDF5 is virtually inactive.
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