HGNC Approved Gene Symbol: GDF3
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38): 12:7,689,784-7,695,775 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12p13.31 | Klippel-Feil syndrome 3, autosomal dominant | 613702 | 3 | |
| Microphthalmia, isolated 7 | 613704 | Autosomal dominant | 3 | |
| Microphthalmia, isolated, with coloboma 6 | 613703 | Autosomal dominant | 3 |
GDF3 is a member of the bone morphogenetic protein (BMP) family. For background information on BMPs, see GDF2 (605120) and Ducy and Karsenty (2000).
By differential screening of cDNAs from retinoic acid (RA) and/or activin A-treated embryonal carcinoma (EC) cells and untreated cells with PCR, followed by 5-prime and 3-prime RACE, Caricasole et al. (1998) isolated a cDNA encoding GDF3. Sequence analysis predicted that the 313-amino acid protein is highly conserved with the mature mouse protein. GDF3 contains a signal peptide but lacks a cysteine thought to be critical for dimerization of the mouse protein. Southern blot analysis confirmed the homology to the mouse gene. Northern blot and RNase protection analyses revealed abundant expression of a 1.1-kb transcript in various EC lines that was differentially regulated by RA treatment. Expression was weak or undetectable in a variety of fetal and adult tissues, as well as in K562 cells. Caricasole et al. (1998) noted that mouse Gdf3 is expressed in thymus, spleen, and bone marrow, tissues they did not test.
By RT-PCR of fetal tissues, Clark et al. (2004) detected high GDF3 expression in ovary and lower expression in kidney, lung, skeletal muscle, and thymus. GDF3 was also expressed in adult testis and ovary, but not in testis from men with Sertoli cell-only syndrome (see 400042). Real-time PCR detected much higher GDF3 expression in seminomas compared with normal testis. GDF3 was expressed by undifferentiated cultured human embryonic stem cells, and expression decreased as differentiation progressed.
Ye et al. (2010) noted that the GDF3 gene contains 2 exons.
By radiation hybrid analysis, Caricasole et al. (1998) mapped the GDF3 gene to chromosome 12p13.1.
Ye et al. (2010) identified heterozygous missense mutations (606522.0001-606522.0004) in the GDF3 gene in patients with ocular anomalies (MCOPCB6, 613703; MCOP7, 613704) and/or skeletal anomalies (Klippel-Feil syndrome-3; 613702), including 1 individual with heterozygous mutations in GDF3 and GDF6 (601147). The authors suggested that multiallelic inheritance of BMP variants may play a role in other developmental disorders.
Andersson et al. (2008) stated that one-third of Gdf3 -/- mouse embryos die with pregastrulation malformations, but those that survive to adulthood show no overt abnormalities. Andersson et al. (2008) found that Gdf3 -/- mice accumulated less adipose tissue than wildtype mice and showed partial resistance to high fat diet-induced obesity despite similar food intake. Gdf3 signaling involved Alk7 (ACVR1C; 608981) and the coreceptor Cripto (TDGF1; 187395), both of which were expressed in adipose tissue. In agreement with a role for Alk7 in Gdf3 signaling, Alk7 -/- mice also showed reduced fat accumulation and partial resistance to diet-induced obesity. Andersson et al. (2008) concluded that GDF3 regulates adipose tissue homeostasis and energy balance under nutrient overload, in part, by signaling through ALK7.
By morpholino knockdown of dvr1, which is the GDF3/GDF1 (602880) zebrafish homolog, Ye et al. (2010) recapitulated ocular and skeletal phenotypes seen in human. Ocular features apparent at 48 hours post fertilization in zebrafish included coloboma and reduced ocular size. Histologic exam revealed consistent reductions in ocular, lenticular, and retinal size, that accord with the microphthalmia seen at earlier stages in live embryos. Skeletal defects ranged from mild to severe tail curvature and reduced tail length.
In a 3-generation North American family with Klippel-Feil syndrome (KFS3; 613702) as well as unilateral iris and retinal coloboma in the proband, Ye et al. (2010) identified a heterozygous 796C-T transition in the GDF3 gene, resulting in an arg266-to-cys (R266C) substitution at a highly conserved residue, which increases the number of cysteine residues in the mature TGF-beta domain. The R266C mutation was not found in 480 control DNA samples. Western blot analysis of transfected COS-7 cell lysates detected reduced amounts of mature R266C-mutant protein in the cytosol with striking reduction in the amount of mature R266C protein in medium. The authors also reported a European male, born of consanguineous parents, with isolated microphthalmia and bilateral coloboma (MCOPCB6; 613703) who was heterozygous for the R266C mutation. The individual's only bony defect was an anomalous right temporal bone. Ye et al. (2010) also described a European mother and daughter with MCOPCB6. The mother showed heterozygosity for the R266C mutation, and her daughter showed double heterozygosity for the R266C mutation and an A199T mutation (601147.0007) in the GDF6 gene. The daughter exhibited a more severe phenotype with nystagmus, bilateral iris coloboma, severe colobomatous microphthalmia, and bilateral foveal hypoplasia. Visual acuity was 20/200. MRI showed abnormally small optic discs with reduced optic nerve diameter, and ERG showed reduced a- and b-wave amplitude.
Ye et al. (2010) described an Asian male, born of consanguineous parents, with unilateral microphthalmia (MCOP7; 613704). His father had no ocular anomalies. Both father and son were heterozygous for a 914T-C transition in the GDF3 gene, resulting in a leu305-to-pro (L305P) substitution in the mature domain. The authors attributed the variation in phenotype to incomplete penetrance, although digenic inheritance could not be excluded. The L305P mutation was not found in 480 control DNA samples. Western blot analysis of transfected COS-7 cell lysates detected mildly reduced amounts of full-length L305P-mutant protein in the cytosol with striking reduction in the amount of mature L305P protein in the media.
In a European female with unilateral microphthalmia (MCOP7; 613704), Ye et al. (2010) identified heterozygosity for a 584G-A transition in the GDF3 gene, resulting in an arg195-to-gln (R195Q) substitution in the prepro domain predicted to result in a charge alteration. The R195Q mutation was not found in 480 control DNA samples. Western blot analysis of transfected COS-7 cell lysates detected mildly reduced amounts of full-length R195Q-mutant protein with more appreciable reduction in the amount of mature R195Q protein.
In an Asian male, born of consanguineous parents, with microphthalmia with coloboma (MCOPCB6; 613703), Ye et al. (2010) identified a heterozygous 820C-T transition in the GDF3 gene, resulting in an arg274-to-trp (R274W) substitution in the mature domain. The R274W mutation changes a conserved hydrophilic residue to a hydrophobic residue, and it was not found in 480 control DNA samples.
Andersson, O., Korach-Andre, M., Reissmann, E., Ibanez, C. F., Bertolino, P. Growth/differentiation factor 3 signals through ALK7 and regulates accumulation of adipose tissue and diet-induced obesity. Proc. Nat. Acad. Sci. 105: 7252-7256, 2008. [PubMed: 18480259] [Full Text: https://doi.org/10.1073/pnas.0800272105]
Caricasole, A. A. D., van Schaik, R. H. N., Zeinstra, L. M., Wierikx, C. D. J., van Gurp, R. J. H. L. M., van den Pol, M., Looijenga, L. H. J., Oosterhuis, J. W., Pera, M. F., Ward, A., de Bruijn, D., Kramer, P., de Jong, F. H., van den Eijnden-van Raaij, A. J. M. Human growth-differentiation factor 3 (hGDF3): developmental regulation in human teratocarcinoma cell lines and expression in primary testicular germ cell tumours. Oncogene 16: 95-103, 1998. [PubMed: 9467948] [Full Text: https://doi.org/10.1038/sj.onc.1201515]
Clark, A. T., Rodriguez, R. T., Bodnar, M. S., Abeyta, M. J., Cedars, M. I., Turek, P. J., Firpo, M. T., Pera, R. A. R. Human STELLAR, NANOG, and GDF3 genes are expressed in pluripotent cells and map to chromosome 12p13, a hotspot for teratocarcinoma. Stem Cells 22: 169-179, 2004. [PubMed: 14990856] [Full Text: https://doi.org/10.1634/stemcells.22-2-169]
Ducy, P., Karsenty, G. The family of bone morphogenetic proteins. Kidney Int. 57: 2207-2214, 2000. [PubMed: 10844590] [Full Text: https://doi.org/10.1046/j.1523-1755.2000.00081.x]
Ye, M., Berry-Wynne, K. M., Asai-Coakwell, M., Sundaresan, P., Footz, T., French, C. R., Abitbol, M., Fleisch, V. C., Corbett, N., Allison, W. T., Drummond, G., Walter, M. A., Underhill, T. M., Waskiewicz, A. J., Lehmann, O. J. Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies. Hum. Molec. Genet. 19: 287-298, 2010. [PubMed: 19864492] [Full Text: https://doi.org/10.1093/hmg/ddp496]