HGNC Approved Gene Symbol: GDF9
Cytogenetic location: 5q31.1 Genomic coordinates (GRCh38): 5:132,861,185-132,866,651 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.1 | ?Premature ovarian failure 14 | 618014 | Autosomal recessive | 3 |
Incerti et al. (1994) described the structure of the mouse growth/differentiation factor-9 (Gdf9) gene. Gdf9 mRNA is synthesized only in the oocyte from the primary 1-layer follicle stage until after ovulation. McGrath et al. (1995) used in situ hybridization methods to show that Gdf9 mRNA is expressed exclusively in mouse oocytes at all stages of follicular development, except in primordial follicles, in both neonatal and adult ovaries. Expression continued after ovulation but disappeared 1.5 days after fertilization.
McGrath et al. (1995) isolated human GDF9 and found that the deduced protein shares 90% sequence identity with the mouse protein in the mature C-terminal portion of the molecule.
Gross (2014) mapped the GDF9 gene to chromosome 5q31.1 based on an alignment of the GDF9 sequence (GenBank BC096228) with the genomic sequence (GRCh37).
Dong et al. (1996) showed that Gdf9, a member of the transforming growth factor-beta superfamily, is required for ovarian folliculogenesis. They analyzed ovaries from female mice deficient in Gdf9 and demonstrated that primordial and primary 1-layer follicles could be formed, but there was a block in follicular development beyond the primary 1-layer follicle stage that led to complete infertility. Oocyte growth and zona pellucida formation proceeded normally, but other aspects of oocyte differentiation were compromised. Thus, the investigators concluded that Gdf9 is the first oocyte-derived growth factor shown to be required for somatic cell function in vivo.
Aaltonen et al. (1999) determined the localization of the GDF9 mRNA and protein during human folliculogenesis by in situ hybridization and immunohistochemical analyses and compared it with that of GDF9B (300247). GDF9 transcripts were not detected in primordial follicles but were abundantly expressed in primary follicles in frozen sections of ovarian cortical tissue obtained at laparoscopic surgery. Human GDF9B transcripts could be detected only in the gonads by RT-PCR analysis, and in situ hybridization studies indicated that GDF9B is not expressed in small primary follicles but rather in the oocytes of late primary follicles. The authors concluded that (1) both GDF9 mRNA and protein are abundantly expressed in oocytes of primary follicles in human ovary, suggesting that the GDF9 transcript is translated at this early stage of folliculogenesis; (2) human GDF9B is specifically expressed in gonads at low levels; (3) expression of GDF9 mRNA begins slightly earlier than that of GDF9B in human oocytes during follicular development; and (4) the results are consistent with the suggestion that GDF9 and GDF9B regulate human folliculogenesis in a manner specific to the ovary.
Filho et al. (2002) compared the pattern and level of expression of GDF9 and BMP15 (300247) mRNA in ovaries from 12 normal-cycling, 5 polycystic ovary syndrome (PCOS; 184700), and 7 polycystic ovary (PCO) individuals. In situ hybridization studies showed that expression of GDF9 and BMP15 was restricted to oocytes in all ovaries examined. A decreased level of GDF9 signal was observed in developing PCOS and PCO oocytes, compared with normal. This difference was evident throughout folliculogenesis, beginning at recruitment initiation and continuing through the small Graafian follicle stage. The results indicated that the expression of GDF9 mRNA is delayed and reduced in PCOS and PCO oocytes during their growth and differentiation phase. Because oocyte-derived GDF9 is crucial for normal folliculogenesis and female fertility, the authors suggested that a dysregulation of oocyte GDF9 expression may contribute to aberrant folliculogenesis in PCOS and PCO women.
Primary Ovarian Failure 14
In a 19-year-old Brazilian woman with primary ovarian failure (POF14; 618014), Franca et al. (2018) identified homozygosity for a 1-bp deletion in the GDF9 gene (601918.0001) that segregated with disease in the family and was not found in controls or public variant databases.
Associations Pending Confirmation
Palmer et al. (2006) studied the frequency of rare variants in GDF9 in families with a history of dizygotic (DZ) twinning (276400). They recruited 3,450 individuals from 915 DZ twinning families (1,693 mothers of twins) and 1,512 controls of Caucasian origin. DNA samples from 279 mothers of DZ twins were screened for rare variants in GDF9 using denaturant high performance liquid chromatography (HPLC). Palmer et al. (2006) found 2 novel insertion/deletions and 4 missense alterations in the GDF9 sequence in mothers of twins. Two of the missense variants were located in the proregion of GDF9, and 2 were in the mature protein region. For each variant, the frequencies were higher in cases compared with controls. The proportion of mothers of DZ twins carrying any variant (4.12%) was significantly higher (P less than 0.0001) than the proportion of carriers in controls (2.29%). The authors suggested that rare GDF9 variants contribute to the likelihood of dizygotic twinning.
Heterozygous and homozygous missense mutations in Bmp15 (300247) and Gdf9 cause elevated fertility and infertility, respectively, in ewes. Using recombinant human BMP15 and GDF9 with mutations corresponding to those identified in sheep, Liao et al. (2004) found that the 2 BMP15 point mutations decreased BMP15 and GDF9 secretion. The GDF9 point mutation had little effect on GDF9 function on its own, but augmented the effects of the BMP15 mutations on secretion of BMP15 and GDF9.
In a 19-year-old Brazilian woman with primary ovarian failure (POF14; 618014), Franca et al. (2018) identified homozygosity for a 1-bp deletion (c.783delC, NM_005260.5) in exon 3 of the GDF9 gene, causing a frameshift predicted to result in a premature termination codon (Ser262HisfsTer2). Her unaffected mother and a fertile sister were heterozygous for the mutation, which was not found in 200 fertile Brazilian women, in 609 elderly Brazilian exomes from the ABraOM database, or in the 1000 Genomes Project, ExAC, or NHLBI Exome Variant Server databases.
Aaltonen, J., Laitinen, M. P., Vuojolainen, K., Jaatinen, R., Horelli-Kuitunen, N., Seppa, L., Louhio, H., Tuuri, T., Sjoberg, J., Butzow, R., Hovatta, O., Dale, L., Ritvos, O. Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B are expressed in oocytes during early folliculogenesis. J. Clin. Endocr. Metab. 84: 2744-2750, 1999. [PubMed: 10443672] [Full Text: https://doi.org/10.1210/jcem.84.8.5921]
Dong, J., Albertini, D. F., Nishimori, K., Kumar, T. R., Lu, N., Matzuk, M. M. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 383: 531-535, 1996. [PubMed: 8849725] [Full Text: https://doi.org/10.1038/383531a0]
Filho, F. L. T., Baracat, E. C., Lee, T. H., Suh, C. S., Matsui, M., Chang, R. J., Shimasaki, S., Erickson, G. F. Aberrant expression of growth differentiation factor-9 in oocytes of women with polycystic ovary syndrome. J. Clin. Endocr. Metab. 87: 1337-1344, 2002. [PubMed: 11889206] [Full Text: https://doi.org/10.1210/jcem.87.3.8316]
Franca, M. M., Funari, M. F. A., Nishi, M. Y., Narcizo, A. M., Domenice, S., Costa, E. M. F., Lerario, A. M., Mendonca, B. B. Identification of the first homozygous 1-bp deletion in GDF9 gene leading to primary ovarian insufficiency by using targeted massively parallel sequencing. Clin. Genet. 93: 408-411, 2018. [PubMed: 29044499] [Full Text: https://doi.org/10.1111/cge.13156]
Gross, M. B. Personal Communication. Baltimore, Md. 4/15/2014.
Incerti, B., Dong, J., Borsani, G., Matzuk, M. M. Structure of the mouse growth/differentiation factor 9 gene. Biochim. Biophys. Acta 1222: 125-128, 1994. [PubMed: 8186260] [Full Text: https://doi.org/10.1016/0167-4889(94)90034-5]
Liao, W. X., Moore, R. K., Shimasaki, S. Functional and molecular characterization of naturally occurring mutations in the oocyte-secreted factors bone morphogenetic protein-15 and growth and differentiation factor-9. J. Biol. Chem. 279: 17391-17396, 2004. [PubMed: 14970198] [Full Text: https://doi.org/10.1074/jbc.M401050200]
McGrath, S. A., Esquela, A. F., Lee, S.-J. Oocyte-specific expression of growth/differentiation factor-9. Molec. Endocr. 9: 131-136, 1995. [PubMed: 7760846] [Full Text: https://doi.org/10.1210/mend.9.1.7760846]
Palmer, J. S., Zhao, Z. Z., Hoekstra, C., Hayward, N. K., Webb, P. M., Whiteman, D. C., Martin, N. G., Boomsma, D. I., Duffy, D. L., Montgomery, G. W. Novel variants in growth differentiation factor 9 in mothers of dizygotic twins. J. Clin. Endocr. Metab. 91: 4713-4716, 2006. [PubMed: 16954162] [Full Text: https://doi.org/10.1210/jc.2006-0970]