Alternative titles; symbols
HGNC Approved Gene Symbol: GDF6
Cytogenetic location: 8q22.1 Genomic coordinates (GRCh38): 8:96,142,333-96,160,806 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q22.1 | Klippel-Feil syndrome 1, autosomal dominant | 118100 | Autosomal dominant | 3 |
| Leber congenital amaurosis 17 | 615360 | Autosomal recessive | 3 | |
| Microphthalmia with coloboma 6, digenic | 613703 | Autosomal dominant | 3 | |
| Microphthalmia, isolated 4 | 613094 | 3 | ||
| Multiple synostoses syndrome 4 | 617898 | Autosomal dominant | 3 |
Growth/differentiation factor-6 is a member of the transforming growth factor-beta (TGFB1; 190180) superfamily (Storm et al., 1994; Chang et al., 1994).
Using degenerate primers to amplify members of the TGF-beta/bone morphogenic protein (BMP) family, Wolfman et al. (1997) obtained a partial human GDF6 clone. The deduced mature protein contains 120 amino acids and shares 99% identity with mouse Gdf6. GDF6 shares a high degree of similarity with GDF5 (601146), GDF7 (604651), and several members of the BMP family (e.g., BMP2; 112261).
By immunohistochemical analysis of mouse retina, Zhang et al. (2012) detected Gdf6 in ganglion cell layer, inner plexiform layer, and retinal pigment epithelia.
By RT-PCR, Bademci et al. (2020) demonstrated expression of Gdf6 in mouse cochlea at embryonic day 17.5 and postnatal day (P) 15. At P15, expression was also present in lung, liver, hippocampus, cortex, and kidney.
Hartz (2006) mapped the GDF6 gene to chromosome 8q22.1 based on an alignment of the GDF6 sequence (GenBank AJ537424, where the gene is designated GDF16) with the genomic sequence (build 36.1).
Settle et al. (2003) found that mouse Gdf5 (601146), 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.
Zhang et al. (2012) found that knockout of Htra1 (602194) expression in mice significantly upregulated expression of Gdf6 and downregulated expression of Vegf (192240) in retinal pigment epithelia.
Colobomata (120200) represent visually impairing ocular closure defects that are associated with a diverse range of developmental anomalies. Asai-Coakwell et al. (2007) characterized a chromosome 8q21.2-q22.1 segmental deletion in a patient with chorioretinal coloboma, and found elements of nonallelic homologous recombination and nonhomologous end joining. The authors demonstrated that the segmental deletion encompassed GDF6. The proband exhibited multiple developmental metabolic defects, including neurodevelopmental impairment (performance IQ 74), bilateral soft tissue syndactyly of the second and third toes, atrial septal defect, and ocular malformations. The latter comprised bilateral retinochoroidal colobomata with optic nerve involvement, plus a unilateral iris coloboma, which reduced vision to counting fingers and 20/50 in the right and left eyes, respectively. Although the proband's father was asymptomatic, ocular examination revealed features of much milder developmental defects that included a minor degree of optic nerve dysplasia, anomalous retinal vascular branching, and small retinochoroidal colobomata. The karyotype of the proband was 46,XX,del(8)(q21.2-q22.1); this abnormality was found in neither parent.
Tassabehji et al. (2008) characterized the location of the inversion inv(8)(q22.2q23.3) breakpoints originally reported by Clarke et al. (1995) in the now expanded 5-generation family with autosomal dominant Klippel-Feil syndrome. The 19.53-Mb inversion was flanked by a distal breakpoint within an intergenic region 1.6 Mb 5-prime from CSMD3 (608399) and 400 kb 3-prime from TRPS1 (604386) and a proximal breakpoint located 623 kb 3-prime of GDF6 within a region known to harbor GDF6 long-range enhancer elements.
In affected members of a family with Leri pleonosteosis (151200), a congenital rheumatic disease, Banka et al. (2015) identified a heterozygous 1-Mb duplication of chromosome 8q22.1. The duplication was confirmed by RT-PCR analysis of cultured dermal fibroblasts from 2 patients. An overlapping 1.2-Mb duplication was found in the proband from a second white family of British origin with the disorder. The overlapping 0.95-Mb region contained 6 genes, but studies of cultured dermal fibroblasts from 2 affected individuals from the first family, aged 77 and 20 years, showed significant overexpression only of the GDF6 gene (40.2- and 13.2-fold increases, respectively). The expression patterns of genes relevant to TGF-beta-mediated extracellular matrix homeostasis differed somewhat between the 2 cultures, and Banka et al. (2015) postulated that the differences may be age-related.
Klippel-Feil Syndrome 1
In affected members of a 3-generation family with autosomal dominant Klippel-Feil syndrome (KFS1; 118100), Tassabehji et al. (2008) identified a heterozygous mutation in the GDF6 gene (A249E; 601147.0001). A different heterozygous mutation (L289P; 601147.0002) was identified in 2 unrelated patients with sporadic Klippel-Feil syndrome.
Isolated Microphthalmia 4
Asai-Coakwell et al. (2009) screened DNA samples from 489 patients with ocular anomalies (microphthalmia, clinical anophthalmia, and coloboma) and 81 patients with vertebral segmentation anomalies for mutations in the GDF6 gene. They identified heterozygosity for 7 different missense mutations in 9 patients (see, e.g., 601147.0001 and 601147.0003-601147.0006), including 5 with isolated microphthalmia (MCOP4; 613094), 1 with coloboma and postaxial polydactyly, and 3 with Klippel-Feil syndrome, including 1 who was the proband of the family previously reported by Tassabehji et al. (2008). Asai-Coakwell et al. (2009) observed a spectrum of ocular and skeletal anomalies in morphant zebrafish, the latter encompassing defective tail formation and altered expression of somite markers noggin1 (NOG; 602991) and noggin2. Gdf6 +/- mice exhibited variable ocular phenotypes compatible with phenotypes observed in patients and zebrafish. Key differences evident between patients and animal models included pleiotropic effects, variable expressivity and incomplete penetrance.
Leber Congenital Amaurosis 17
Asai-Coakwell et al. (2013) analyzed the GDF6 gene in 279 DNA samples from patients diagnosed with Leber congenital amaurosis (LCA17; 615360) or juvenile retinitis pigmentosa (JRP) who were negative for mutation in known causative genes, and identified compound heterozygosity for the A249E substitution (601147.0001) and another missense mutations (D57H; 601147.0008) in 1 LCA proband. Three additional heterozygous GDF6 missense mutation were identified in the LCA/JRP cohort: A249E, A199T (601147.0007), and E292D (601147.0009). Asai-Coakwell et al. (2013) hypothesized that a second variant in the TGF-beta (see 190180) pathway was present in the probands with a heterozygous GDF6 mutation, but exome sequencing yielded incomplete coverage across open-reading frames of BMP (see 112261) ligands, preventing identification of known heterozygous mutations.
Multiple Synostoses Syndrome 4
In a large 6-generation Chinese family with multiple synostoses syndrome (SYNS4; 617898), Wang et al. (2016) identified heterozygosity for a missense mutation in the GDF6 gene (Y444N; 601147.0010) that segregated fully with disease and was not found in ethnically matched controls or in public variant databases. Functional analysis indicated that the Y444N substitution represents a gain-of-function mutation.
In a 4-generation family with multiple synostoses syndrome, Terhal et al. (2018) identified heterozygosity for a missense mutation (S429R; 601147.0011) that segregated with disease and was not found in public variant databases.
Deafness, Autosomal Recessive 118, with Cochlear Aplasia
In 2 male cousins and an unrelated male patient from consanguineous Turkish families with congenital profound sensorineural deafness and cochlear aplasia (DFNB118; 619553), who were negative for mutation in known deafness-associated genes, Bademci et al. (2020) identified homozygosity for overlapping deletions on chromosome 8, involving 221,739 bp in the 2 cousins (chr8:96,582,049-96,803,788, GRCh37) and 338,135 bp in the other patient (chr8:96,596,661-96,934,796, GRCh37). The presence and segregation of the deletions was confirmed by Sanger sequencing in both families, and neither deletion was found in 1,025 Turkish controls or in the gnomAD, Genomic Variants, or DECIPHER databases. Analysis of early otic lineage cells derived from patient and control stem cells revealed that of the 14 genes within 1 Mb of the 200-kb overlapping deletion region, GDF6 was the only gene to show significant differences in expression between patient and control cells. In addition, the authors dissected and paint-filled the inner ears of Gdf6-knockout mice and observed absence of the entire cochlea, with normal vestibular anatomy. The authors noted that there were multiple highly conserved DNA sequences and active chromatin positions within the overlapping deleted region in the Turkish families, suggesting that the region contains enhancers for the regulation of gene expression.
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.
Hanel and Hensey (2006) demonstrated in Xenopus that inhibition of gdf6 results in abnormalities in ocular development.
Asai-Coakwell et al. (2007) showed that inhibition of gdf6a in zebrafish accurately recapitulated the phenotype of a proband with a chromosome 8q21.2-q22.1 segmental deletion and chorioretinal coloboma. The spectrum of disorders generated by morpholino inhibition and the more severe defects (microphthalmia and anophthalmia) observed at higher doses illustrated the key role of GDF6 in ocular development. The results underscored the usefulness of integrated clinical and molecular investigation of patients with chromosomal anomalies.
Tassabehji et al. (2008) reported that knockdown of the Gdf6 gene in Xenopus laevis resulted in axial and ocular defects. The most prevalent phenotype of abnormal anterior axial alignments resulted in embryos with head positions deviating in the vertical and lateral plane.
Asai-Coakwell et al. (2013) generated mice with a targeted deletion of Gdf6 exon 2 and observed that heterozygotes exhibited abnormal electroretinograms with up to 66% decreases in the bipolar cell-driven b-wave and 54% decreases in the photoreceptor-mediated a-wave amplitudes, as well as 3 to 27% reduced photopic flicker fusion, findings compatible with a role for GDF6 in retinal function. Examination of adult zebrafish homozygous for a Gdf6 S55X mutation showed microphthalmia and misshapen irides. Histologic analysis of homozygous mutants at 2 weeks of age demonstrated profound alterations to the morphology of individual photoreceptor subtypes, including red/green and UV cones. Actin and nuclear staining at later timepoints revealed loss of normal retinal lamination, and immunohistochemistry showed disorganization of Muller glial cells. Cone photoreceptors in homozygous mutant adult zebrafish were consistently dysmorphic and reduced in abundance. In addition, significantly increased retinal apoptosis was observed in Gdf6 mutant mice and zebrafish compared to wildtype animals; treatment of mutant zebrafish embryos with the antiapoptotic compound P7C3 rescued the retinal apoptosis without evidence of toxicity. Asai-Coakwell et al. (2013) stated that this was the first evidence of perturbed TGF-beta (see 190180) signaling in retinal disease.
Bademci et al. (2020) dissected and paint-filled the inner ears of Gdf6-knockout mice and observed absence of the entire cochlea, with normal vestibular anatomy.
Klippel-Feil Syndrome 1
In affected members of a 3-generation family with autosomal dominant Klippel-Feil syndrome (KFS1; 118100), Tassabehji et al. (2008) identified a heterozygous 746C-A transversion in exon 2 of the GDF6 gene, resulting in an ala249-to-glu (A249E) substitution in the prodomain. The mutation was not found in 708 control chromosomes. The phenotype was characterized primarily by fusion of vertebral bodies C2 and C3. The authors suggested functional haploinsufficiency as the pathogenetic mechanism.
Isolated Microphthalmia 4
Asai-Coakwell et al. (2009) screened the GDF6 gene in patients with ocular and vertebral anomalies, and identified heterozygosity for the A249E mutation in 2 probands, 1 of whom was a patient with isolated microphthalmia (MCOP4; 613094). The other patient had coloboma and postaxial polydactyly without vertebral defects, and her unaffected mother also carried the mutation, demonstrating incomplete penetrance. Functional studies showed significantly reduced reporter activity and reduced levels of mature ligand with mutant GDF6 compared to wildtype, indicating that A249E represents a hypomorphic mutation. The mutation was not found in 366 controls.
Leber Congenital Amaurosis 17
In a female patient with Leber congenital amaurosis (LCA17; 615360), Asai-Coakwell et al. (2013) identified compound heterozygosity for the A249E mutation in the GDF6 gene and a c.169G-C transversion, resulting in an asp57-to-his (D57H; 601147.0008) substitution. The patient had vision limited to detection of hand motions with an extinguished electroretinogram (ERG) typical of the LCA phenotype; she did not have other ocular or systemic phenotypes, but the authors noted that she had not undergone radiologic imaging to detect milder GDF6-induced skeletal disease. Her clinically unaffected mother, who was heterozygous for the A249E mutation, exhibited a delayed rod b-wave implicit time on ERG; similarly, her father, who was heterozygous for D57H, showed reduced b-wave amplitude. The D57H mutation was absent from 1,500 control chromosomes, whereas the A249E mutation was found in 4. Expression analysis showed a 36% and 56% reduction in A249E mutant preproprotein and mature ligand levels compared to wildtype, and reporter assays showed that the A249E mutant has only 50% of wildtype activity. Levels of D57H preproprotein and mature ligand were markedly reduced, with an 80% and 97% reduction in the cytosolic fraction, respectively, and a 97% and 99% reduction in the media fraction; the D57H mutant had only 24% of wildtype activity in reporter assays. Asai-Coakwell et al. (2013) also identified heterozygosity for the A249E mutation in a female patient from an LCA/juvenile retinitis pigmentosa cohort, who had inherited the mutation from her unaffected father.
In 2 unrelated patients with sporadic Klippel-Feil syndrome (KFS1; 118100), Tassabehji et al. (2008) identified a heterozygous 866T-C transition in exon 2 of the GDF6 gene, resulting in a leu289-to-pro (L289P) substitution in a conserved residue in the prodomain. The mutation was not found in 708 control chromosomes. One patient was an adult male with short neck, mirror movements, and left Sprengel anomaly. The second patient was a fetus assessed following termination of pregnancy for antenatal diagnosis of multiple segmentation abnormalities affecting the entire spine and ribs, as well as multiple other congenital anomalies.
In a patient with hemivertebrae and rib malformations, or Klippel-Feil syndrome (KFS1; 118100), Asai-Coakwell et al. (2009) identified heterozygosity for a 1271A-G transition in exon 2 of the GDF6 gene, predicted to result in a lys424-to-arg (K424R) substitution at a highly conserved residue in the propeptide domain. Functional studies showed significantly reduced reporter activity and reduced levels of mature ligand with mutant GDF6 compared to wildtype, indicating that K424R represents a hypomorphic mutation. The mutation was not found in 366 controls. The authors noted that in addition to skeletal anomalies, this patient also had fused (horseshoe) kidney.
In a patient with Klippel-Feil syndrome (KFS1; 118100), described as spondylothoracic dysostosis, Asai-Coakwell et al. (2009) identified heterozygosity for a 125G-T transversion in exon 1 of the GDF6 gene, predicted to result in a gly42-to-val (G42V) substitution at a conserved residue in the propeptide domain. The mutation was not found in 366 controls.
In a patient with isolated microphthalmia (MCOP4; 613094), Asai-Coakwell et al. (2009) identified heterozygosity for a 758A-T transversion in exon 1 of the GDF6 gene, predicted to result in a gln253-to-leu (Q253L) substitution at a conserved residue in the propeptide domain. The mutation was found in the patient's unaffected mother, indicating incomplete penetrance, but was not detected in 366 controls. The authors noted that in addition to the eye findings, this patient had a single testis.
In a patient with unilateral isolated microphthalmia (MCOP4; 613094), Asai-Coakwell et al. (2009) identified heterozygosity for a 980C-A transversion in exon 2 of the GDF6 gene, predicted to result in a pro327-to-his (P327H) substitution at a conserved residue in the propeptide domain. The mutation was also found in the patient's father, indicating incomplete penetrance, but was not detected in 366 controls.
Microphthalmia/Coloboma 6
Ye et al. (2010) described a European female with severe colobomatous microphthalmia, bilateral iris coloboma, mixed horizontal and rotatory nystagmus, bilateral foveal hypoplasia, and small optic discs with reduced optic nerve diameter (MCOPCB6; 613703). They identified double heterozygosity for an A199T mutation in the GDF6 gene and an R266C mutation in the GDF3 gene (606522.0001). Her mildly affected mother was heterozygous for the GDF3 mutation only. The authors suggested that multiallelic inheritance of BMP variants may play a role in other developmental disorders.
Leber Congenital Amaurosis 17
In a female proband diagnosed with Leber congenital amaurosis (LCA17; 615360), Asai-Coakwell et al. (2013) identified heterozygosity for the A199T substitution in the GDF6 gene, inherited from her clinically unaffected father. The mutation was not found in 650 control chromosomes. Western blot showed a 47% and a 4% increase in expression of the A199T mutant in the whole-cell lysate and media fractions, respectively, compared to wildtype; however, reporter assays demonstrated significantly reduced activation with the A199T mutant (56% decrease) compared to wildtype.
For discussion of the asp57-to-his (D57H) mutation in the GDF6 gene that was found in compound heterozygous state in a patient with Leber congenital amaurosis (LCA17; 615360) by Asai-Coakwell et al. (2013), see 601147.0001.
In a female patient diagnosed with Leber congenital amaurosis (LCA17; 615360), Asai-Coakwell et al. (2013) identified heterozygosity for a c.876G-A transition in the GDF6 gene, resulting in a glu292-to-asp (E292D) substitution at a highly conserved residue. The mutation was also present in her clinically unaffected mother, but was not found in 1,500 control chromosomes. Western blot showed a 37% and a 56% increase in expression of the E292D mutant in the whole-cell lysate and media fractions, respectively, compared to wildtype; however, reporter assays demonstrated significantly reduced activation with the E292D mutant (69% decrease) compared to wildtype.
In affected members of a large 6-generation Chinese family with multiple synostoses syndrome-4 (SYNS4; 617898), Wang et al. (2016) identified heterozygosity for a c.1330T-A transversion in the GDF6 gene, resulting in a tyr444-to-asn (Y444N) substitution at a highly conserved residue within the NOG (602991)-GDF6 binding interface. The mutation segregated fully with disease in the family and was not found in 105 Chinese controls or in the 1000 Genomes Project or NHLBI Exome Sequencing Project databases. Functional analysis in C2C12 cells showed that the Y444N mutant stimulated higher alkaline phosphatase (ALP) and Smad1/5/8 (see 601595) reporter activity than wildtype GDF6, suggesting a gain of function. In micromass cultures of immortalized limb bud cells, the Y444N mutant displayed increased chondrogenic activity compared to wildtype GDF6. The addition of NOG inhibited wildtype GDF6-induced ALP activity in a dose-dependent manner, whereas it had no effect on mutant GDF6. The authors concluded that the Y444N mutation renders GDF6 insensitive to NOG, resulting in exaggerated BMP (see 112264) signaling and chondrogenic activity at sites where GDF6 and NOG are coexpressed.
In affected members of a 4-generation family with multiple synostoses syndrome-4 (SYNS4; 617898), Terhal et al. (2018) identified heterozygosity for a c.1287C-A transversion in the GDF6 gene, resulting in a ser429-to-arg (S429R) substitution at a highly conserved residue within the C-terminal transforming growth factor-beta (see 190180) domain. The mutation segregated with disease in the family and was not found in the ExAC or GoNL databases.
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