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Link to original content: https://omim.org/entry/610934
Alternative titles; symbols
HGNC Approved Gene Symbol: NOBOX
Cytogenetic location: 7q35 Genomic coordinates (GRCh38) : 7:144,396,900-144,410,227 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q35 | Premature ovarian failure 5 | 611548 | Autosomal dominant | 3 |
NOBOX is a homeobox gene that is preferentially expressed in oocytes. In mice, it is essential for folliculogenesis and regulation of oocyte-specific genes (Huntriss et al., 2006).
NOBOX is a member of the paired (PRD)-like homeobox gene family of transcription factors. NOBOX is expressed in early embryos and is thought to play a role in the regulation of embryo genome activation and preimplantation embryo development (Madissoon et al., 2016).
Suzumori et al. (2002) cloned mouse Nobox and identified its human homolog by database analysis. The mouse and human proteins share 92% identity in the homeodomain region. RT-PCR and Northern blot analyses of mouse tissues detected Nobox expression only in testis and ovary. In situ hybridization of mouse ovaries revealed Nobox mRNA in primordial and growing oocytes.
By PCR of a human ovarian follicle cDNA library, Huntriss et al. (2006) obtained a partial NOBOX cDNA. The deduced protein contains a homeodomain that includes a nuclear localization signal. Nested PCR detected NOBOX expression in ovary, testis, and pancreas. NOBOX was expressed from the primordial follicle stage through to the metaphase II oocytes. Expression was lower in preimplantation embryos and was not observed in granulosa cells.
Madissoon et al. (2016) described 9 human PRD-like homeobox domain genes, including NOBOX, found in human embryos. The homeodomain in PRD-like homeobox genes consists of approximately 60 amino acids and folds into an N-terminal arm and 3 alpha-helices.
Huntriss et al. (2006) determined that the NOBOX gene contains at least 5 exons.
By genomic sequence analysis, Suzumori et al. (2002) mapped the NOBOX gene to chromosome 7q35. They mapped the mouse gene to chromosome 6 in region that shows homology of synteny to human chromosome 7q35. The CLCN1 (118425) and CASP2 (600639) genes flank the NOBOX gene in both mouse and human.
Overexpression of 9 PRD-like homeobox genes, including NOBOX, in embryonic stem cells (ESCs) by Madissoon et al. (2016) confirmed that the genes are mainly transcription activators or repressors and have distinct target genes that are activated during human preimplantation development. Madissoon et al. (2016) found enrichment of a 36-bp motif upstream of the transcription start site for genes regulated by most of the PRD-like homeobox genes. The target genes downregulated by DUXB (618698), DPRX (611165), TPRX2 (620360), and NOBOX shared significant overlap.
Qin et al. (2007) sequenced the NOBOX gene in 96 Caucasian women with premature ovarian failure (POF) and identified heterozygosity for a mutation (R355H; 610934.0001) in a 35-year-old woman with premature ovarian failure (POF5; 611548) who had menarche at age 11 years, entered menopause at age 32, and had an elevated FSH level. The mutation was not found in 278 Caucasian female controls.
In 11 (6.2%) of 178 probands with POF, Bouilly et al. (2011) identified heterozygosity for 1 nonsense (R303X; 610934.0002) and 4 missense mutations (610934.0003-610934.0006) in the NOBOX gene. Functional analysis demonstrated a 50% reduction in transcriptional activity with all 5 mutations, due to disruption of binding ability. Noting differences in phenotype among patients carrying the same mutation and even between sisters, with some having primary amenorrhea with absent or delayed puberty and others undergoing normal puberty with secondary amenorrhea (see, e.g., 610934.0004), Bouilly et al. (2011) suggested that POF might represent an oligogenic phenotype.
Bouilly et al. (2015) analyzed the NOBOX gene in a new cohort of 213 women with 46,XX primary ovarian insufficiency and identified 5 mutations in 12 (5.6%) of the patients (see, e.g., 610934.0003-610934.0004). Ten of the mutation-positive women underwent puberty but experienced secondary amenorrhea in the third or fourth decade of life, whereas 2 had primary amenorrhea and did not undergo puberty.
Rajkovic et al. (2004) found that Nobox-null mice were born at the expected mendelian ratio. Nobox-null males were fertile and lacked gross anatomic abnormalities, but Nobox-null females were infertile with atrophic ovaries. Lack of Nobox accelerated postnatal oocyte loss and abolished the transition from primordial to growing follicles. Follicles were replaced by fibrous tissue in a manner similar to nonsyndromic ovarian failure in women. Genes preferentially expressed in oocytes, including Oct4 (POU5F1; 164177) and Gdf9 (601918), were downregulated in Nobox-null mice, whereas ubiquitously expressed genes were unaffected.
In a 35-year-old Caucasian woman with premature ovarian failure (POF5; 611548), Qin et al. (2007) identified heterozygosity for a c.1064G-A transition in exon 6 of the NOBOX gene, resulting in an arg355-to-his (R355H) substitution within the highly conserved homeodomain region. EMSA analysis confirmed that the R355H mutation disrupted NOBOX homeodomain binding and had a dominant-negative effect on the binding of wildtype NOBOX to DNA. The mutation was not found in 278 Caucasian female controls.
In a woman who underwent normal puberty but experienced secondary amenorrhea at 28 years of age (POF5; 611548), Bouilly et al. (2011) identified heterozygosity for a c.907C-T transition in exon 5 of the NOBOX gene, resulting in an arg303-to-ter (R303X) substitution predicted to cause a major deletion of the homeodomain. Translation analysis confirmed that the R303X protein lacks the C-terminal part and has a total length of 303 amino acids rather than the normal 490. EMSA analysis showed that the R303X mutant disrupts NOBOX binding; studies in both HEK293T and COS-7 cells revealed a dramatic and significant decrease in the transactivation of the GDF9 (601918) reporter gene compared to wildtype. The patient's ovaries appeared normal by ultrasound; a cyst was observed and was found to be a luteinized cyst by histology.
In a Guinean woman with primary amenorrhea and absent puberty and a Senegalese woman who underwent normal puberty but experienced secondary amenorrhea at 21 years of age (POF5; 611548), Bouilly et al. (2011) identified heterozygosity for a c.271G-T transversion in exon 3 of the NOBOX gene, resulting in a gly91-to-trp (G91W) substitution. The mutation, which was not found in 362 ethnically matched controls, was also absent in both unaffected parents of the Senegalese patient, indicating that the mutation arose de novo. DNA was not available from the parents of the Guinean woman. EMSA analysis showed that the G91W mutant disrupts NOBOX binding; studies in both HEK293T and COS-7 cells revealed a dramatic and significant decrease in the transactivation of the GDF9 (601918) reporter gene compared to wildtype. The patients' ovaries were either small or not visualized on ultrasound, and no follicles were seen; histology confirmed the absence of follicles in the Senegalese patient.
In 2 unrelated women with primary amenorrhea and absent puberty and 5 unrelated women who underwent normal puberty but experienced secondary amenorrhea, Bouilly et al. (2015) identified heterozygosity for the G91W mutation in the NOBOX gene.
In 2 sisters from the Democratic Republic of Congo and 2 unrelated women from Mali and the French Caribbean who had premature ovarian failure-5 (POF5; 611548), Bouilly et al. (2011) identified heterozygosity for a c.349C-T transition in exon 4 of the NOBOX gene, resulting in an arg117-to-trp (R117W) substitution at a residue conserved in primates. EMSA analysis showed that the R117W mutant disrupts NOBOX binding; studies in both HEK293T and COS-7 cells revealed a dramatic and significant decrease in the transactivation of the GDF9 (601918) reporter gene compared to wildtype. One of the sisters had primary amenorrhea and delayed puberty, whereas the other underwent normal puberty but experienced secondary amenorrhea at 23 years of age. The Malian woman had normal puberty with secondary amenorrhea at 16 years of age, whereas the French Caribbean woman had primary amenorrhea and delayed puberty. On ultrasound, ovaries were normal to small in 3 patients, and 1 had streak gonads with a dermoid cyst. Only 1 of the patients exhibited follicles on ultrasound, which were primordial by histology; another patient (her sister), in whom follicles were not detected by ultrasound, had primary follicles on histology.
In 2 unrelated Caucasian women who underwent normal puberty but experienced secondary amenorrhea (POF5; 611548) at 26 and 30 years of age, respectively, Bouilly et al. (2011) identified heterozygosity for the R117W mutation in the NOBOX gene.
In 4 unrelated Caucasian women who underwent normal puberty but experienced secondary amenorrhea (POF5; 611548) at 26 to 36 years of age, Bouilly et al. (2011) identified heterozygosity for a c.1025G-C transversion in exon 5 of the NOBOX gene, resulting in a ser342-to-thr (S342T) substitution within the 32-amino-acid primate-specific region. EMSA analysis showed that the S342T mutant disrupts NOBOX binding; studies in both HEK293T and COS-7 cells revealed a dramatic and significant decrease in the transactivation of the GDF9 (601918) reporter gene compared to wildtype. The ovaries were normal to small by ultrasound, with follicles present in only 2 patients; absence of follicles was confirmed by histology in 1 woman.
In a Caucasian woman who underwent normal puberty but experienced secondary amenorrhea at 37 years of age (POF5; 611548), Bouilly et al. (2011) identified heterozygosity for a c.1048G-T transversion in exon 6 of the NOBOX gene, resulting in a val350-to-leu (V350L) substitution within the 32-amino-acid primate-specific region. EMSA analysis showed that the V350L mutant disrupts NOBOX binding; studies in both HEK293T and COS-7 cells revealed a dramatic and significant decrease in the transactivation of the GDF9 (601918) reporter gene compared to wildtype. Ultrasound showed normal-sized ovaries with follicles present.
Bouilly, J., Bachelot, A., Broutin, I., Touraine, P., Binart, N. Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort. Hum. Mutat. 32: 1108-1113, 2011. [PubMed: 21837770] [Full Text: https://doi.org/10.1002/humu.21543]
Bouilly, J., Roucher-Boulez, F., Gompel, A., Bry-Gauillard, H., Azibi, K., Beldjord, C., Dode, C., Bouligand, J., Guiochon Mantel, A., Hecart, A.-C., Delemer, B., Young, J., Binart, N. New NOBOX mutations identified in a large cohort of women with primary ovarian insufficiency decrease KIT-L expression. J. Clin. Endocr. Metab. 100: 994-1001, 2015. [PubMed: 25514101] [Full Text: https://doi.org/10.1210/jc.2014-2761]
Huntriss, J., Hinkins, M., Picton, H. M. cDNA cloning and expression of the human NOBOX gene in oocytes and ovarian follicles. Molec. Hum. Reprod. 12: 283-289, 2006. [PubMed: 16597639] [Full Text: https://doi.org/10.1093/molehr/gal035]
Madissoon, E., Jouhilahti, E.-M., Vesterlund, L., Tohonen, V., Krjutskov, K., Petropoulos, S., Einarsdottir, E., Linnarsson, S., Lanner, F., Mansson, R., Hovatta, O., Burglin, T. R., Katayama, S., Kere, J. Characterization and target genes of nine human PRD-like homeobox domain genes expressed exclusively in early embryos. Sci. Rep. 6: 28995, 2016. Note: Electronic Article. Erratum: Sci. Rep. 6: 32053, 2016. [PubMed: 27412763] [Full Text: https://doi.org/10.1038/srep28995]
Qin, Y., Choi, Y., Zhao, H., Simpson, J. L., Chen, Z.-J., Rajkovic, A. NOBOX homeobox mutation causes premature ovarian failure. Am. J. Hum. Genet. 81: 576-581, 2007. [PubMed: 17701902] [Full Text: https://doi.org/10.1086/519496]
Rajkovic, A., Pangas, S. A., Ballow, D., Suzumori, N., Matzuk, M. M. NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression. Science 305: 1157-1159, 2004. [PubMed: 15326356] [Full Text: https://doi.org/10.1126/science.1099755]
Suzumori, N., Yan, C., Matzuk, M. M., Rajkovic, A. Nobox is a homeobox-encoding gene preferentially expressed in primordial and growing oocytes. Mech. Dev. 111: 137-141, 2002. [PubMed: 11804785] [Full Text: https://doi.org/10.1016/s0925-4773(01)00620-7]