NOBOX

Last updated
NOBOX
Identifiers
Aliases NOBOX , OG-2, OG2, OG2X, POF5, TCAG_12042, NOBOX oogenesis homeobox
External IDs OMIM: 610934 MGI: 108011 HomoloGene: 51066 GeneCards: NOBOX
Orthologs
SpeciesHumanMouse
Entrez

135935

18291

Ensembl

ENSG00000106410
ENSG00000285328

ENSMUSG00000029736

UniProt

O60393

Q8VIH1

RefSeq (mRNA)

NM_001080413

NM_130869

RefSeq (protein)

NP_001073882

NP_570939

Location (UCSC) Chr 7: 144.4 – 144.41 Mb Chr 6: 43.28 – 43.29 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Homeobox protein NOBOX, also known as newborn ovary homeobox protein, is a protein that in humans is encoded by the NOBOX gene. [5] [6] [7] The official symbol (NOBOX) and the official full name (NOBOX oogenesis homeobox) are maintained by the HGNC. The NOBOX gene is conserved in chimpanzee, Rhesus monkey, cow, mouse, and rat. There are 175 organisms that have orthologs with human gene NOBOX. It is capable of regulating other genes that are important in the development of follicles. Follicles do not develop and oocytes decrease in its absence which lead to infertility. [8]

Contents

Discovery

NOBOX is an in silico subtraction discovery when Suzumori et al. searched for novel genes involved in early mammalian folliculogenesis in 2002. It is one of the several genes that appeared in the search in expressed sequence tag (EST) databases of mouse. [6] It was then cloned and characterised for its genomic structure.

Gene location

The human NOBOX is located in chromosome 7q35 while the mouse NOBOX is in proximal chromosome 6.

Protein structure

The human NOBOX is a 14 kb protein and encoded by 8 exons. [6] It has a proline rich C terminus and contains putative SH3 and WW domains. [9] This C terminus is believed to be critical in its transcriptional activities when bound to oocyte-specific genes. [10] NOBOX belongs to the family of proteins that contains homeodomain. Homeodomain is a stretch of 32 specific amino acids in primates downstream the NOBOX Arg303 residue and is very well-conserved among the species. [11] It contains an asparagine residue at position 51 which is important for its interactions with DNA base pairs. [12] [13] [14]

Function

NOBOX is a homeobox gene that is preferentially expressed in oocytes. In mice, it is essential for folliculogenesis and regulation of oocyte-specific genes. [7] Regulation of these oocyte-specific genes is thru direct binding of NOBOX to its promoter regions via the specific consensus sequences, the NOBOX DNA binding elements (NBEs). There are three NBEs that have been identified: 5'-TAATTG-3', 5'-TAGTTG-3', and 5'-TAATTA-3'. [10] Knockout study of NOBOX against wild-type ovaries in newborn female mice revealed that 74% (28/38 genes) were downregulated more than 5-fold and 15% (5/33 genes) were upregulated more than 5-fold. [15] However, microRNA population is not affected by NOBOX in newborn ovaries. NOBOX also plays an important role in the suppression of male-determining genes such as Dmrt1 . [15] Its deficiency can cause rapid loss of postnatal oocytes and during its absence in female mice, follicles are replaced by fibrous tissue. [6]  Recently, a new role of NOBOX in controlling the G2/M arrest was discovered. [16]

Mutations and clinical significance

A mutation in the NOBOX gene is associated with premature ovarian failure (POF), also known as premature ovarian insufficiency (POI). [17] It is a condition which ovaries loss its normal function before the age of 40. It is a heritable disease in up to 30% of patients which is characterised by secondary infertility, amenorrhea, hypoestrogenism, and elevated follicle-stimulating hormone levels in the serum (FSH>40IU/liter). [18] [19] It affects ≈1% of women below 40 years old. [20] A study conducted on 96 white women with POF revealed one case of heterozygous mutation in the NOBOX homeodomain, p.Arg355His, in one patient. [17] This mutation was absent in the control population and significantly disrupts the binding of NOBOX to the NBE. Arg355 is critical to DNA binding and is conserved in the homeodomain of the NOBOX from zebrafish to humans. Moreover, its significant negative effect suggests that NOBOX homeodomain may function as a dimer but its rare occurrence suggests a low contribution to POF. Further investigations on POF were conducted on Caucasian, African, Chinese, and Japanese women diagnosed with POF. Several NOBOX loss-of-function mutations were observed in Caucasian and African women accounting to 6.2%, 5.6% and 6.4%. [11] [21] [22] These results suggest that NOBOX gene is a strong autosomal candidate for POF and its genetic mechanism involves haploinsufficiency. However, these mutations were not found in Chinese and Japanese women making it a less common explanation for POF in the region. [23] [24]

The POF syndrome is a highly heterogenous clinical disorder but a recent study showed the first homozygous mutation associated with NOBOX loss-of-function. [16] One patient out of 96 population diagnosed with POF in China was found with one novel homozygous truncating variant in the NOBOX gene. This truncated variant caused a defective transcriptional activation of GDF9, a well-known target of NOBOX, which led to the lost ability of NOBOX to induce G2/M arrest. This finding disagrees that mutation is a less common explanation for POF in Asian population.

Understanding the mutations in NOBOX homeodomain is important to researchers and clinicians to develop diagnostic and therapeutic approaches for POF such as genetic control of mammalian reproductive life-span, regulation of fertility, and generation of mature eggs in the lab. [8]

Interactions

  1. GDF9 [10] [25]
  2. POU5F1 [6] [10] [8]
  3. DNMT10 [8]
  4. FOXL2 [26]
  5. FIGLA [8]
  6. RSPO2 [27]
  7. DMRT1 [19]

Related Research Articles

<span class="mw-page-title-main">Ovary</span> Female reproductive organ that produces egg cells

The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus. There is an ovary found on the left and the right side of the body. The ovaries also secrete hormones that play a role in the menstrual cycle and fertility. The ovary progresses through many stages beginning in the prenatal period through menopause. It is also an endocrine gland because of the various hormones that it secretes.

<span class="mw-page-title-main">Gonad</span> Gland that produces sex cells

A gonad,sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sperm in the form of spermatozoa. The female gonad, the ovary, produces egg cells. Both of these gametes are haploid cells. Some hermaphroditic animals have a type of gonad called an ovotestis.

<span class="mw-page-title-main">Oogenesis</span> Egg cell production process

Oogenesis, ovogenesis, or oögenesis is the differentiation of the ovum into a cell competent to further develop when fertilized. It is developed from the primary oocyte by maturation. Oogenesis is initiated in the embryonic stage.

<span class="mw-page-title-main">Ovarian follicle</span> Structure containing a single egg cell

An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, those with ovaries have approximately 200,000 to 300,000 follicles, each with the potential to release an egg cell (ovum) at ovulation for fertilization. These eggs are developed once every menstrual cycle with around 450–500 being ovulated during a woman's reproductive lifetime.

<span class="mw-page-title-main">Granulosa cell</span>

A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete in the ovary of mammals.

<span class="mw-page-title-main">Anti-Müllerian hormone</span> Mammalian protein found in humans

Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differentiation and folliculogenesis. In humans, it is encoded by the AMH gene, on chromosome 19p13.3, while its receptor is encoded by the AMHR2 gene on chromosome 12.

<span class="mw-page-title-main">Folliculogenesis</span> Process of maturation of primordial follicles

In biology, folliculogenesis is the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains an immature oocyte. Folliculogenesis describes the progression of a number of small primordial follicles into large preovulatory follicles that occurs in part during the menstrual cycle.

<span class="mw-page-title-main">Ovarian reserve</span>

Ovarian reserve is a term that is used to determine the capacity of the ovary to provide egg cells that are capable of fertilization resulting in a healthy and successful pregnancy. With advanced maternal age the number of egg cell that can be successfully recruited for a possible pregnancy declines, constituting a major factor in the inverse correlation between age and female fertility.

<span class="mw-page-title-main">Growth differentiation factor-9</span> Protein-coding gene in the species Homo sapiens

Growth/differentiation factor 9 is a protein that in humans is encoded by the GDF9 gene.

<span class="mw-page-title-main">Follicular atresia</span>

Follicular atresia refers to the process in which a follicle fails to develop, thus preventing it from ovulating and releasing an egg. It is a normal, naturally occurring progression that occurs as mammalian ovaries age. Approximately 1% of mammalian follicles in ovaries undergo ovulation and the remaining 99% of follicles go through follicular atresia as they cycle through the growth phases. In summary, follicular atresia is a process that leads to the follicular loss and loss of oocytes, and any disturbance or loss of functionality of this process can lead to many other conditions.

Primary ovarian insufficiency (POI) is the partial or total loss of reproductive and hormonal function of the ovaries before age 40 because of follicular dysfunction or early loss of eggs. POI can be seen as part of a continuum of changes leading to menopause that differ from age-appropriate menopause in the age of onset, degree of symptoms, and sporadic return to normal ovarian function. POI affects approximately 1 in 10,000 women under age 20, 1 in 1,000 women under age 30, and 1 in 100 of those under age 40. A medical triad for the diagnosis is amenorrhea, hypergonadotropism, and hypoestrogenism.

<span class="mw-page-title-main">Bone morphogenetic protein 15</span> Protein-coding gene in humans

Bone morphogenetic protein 15 (BMP-15) is a protein that in humans is encoded by the BMP15 gene. It is involved in folliculogenesis, the process in which primordial follicles develop into pre-ovulatory follicles.

Poor ovarian reserve is a condition of low fertility characterized by 1): low numbers of remaining oocytes in the ovaries or 2) possibly impaired preantral oocyte development or recruitment. Recent research suggests that premature ovarian aging and premature ovarian failure may represent a continuum of premature ovarian senescence. It is usually accompanied by high FSH levels.

<span class="mw-page-title-main">FOXL2</span> Transcription factor gene of the FOX family

Forkhead box protein L2 is a protein that in humans is encoded by the FOXL2 gene.

Ovarian tissue cryopreservation is cryopreservation of tissue of the ovary of a female.

<span class="mw-page-title-main">FIGLA</span> Protein-coding gene in the species Homo sapiens

Folliculogenesis-specific basic helix-loop-helix, also known as factor in the germline alpha (FIGalpha) or transcription factor FIGa, is a protein that in humans is encoded by the FIGLA gene. The FIGLA gene is a germ cell-specific transcription factor preferentially expressed in oocytes that can be found on human chromosome 2p13.3.

Ovarian follicle activation can be defined as primordial follicles in the ovary moving from a quiescent (inactive) to a growing phase. The primordial follicle in the ovary is what makes up the “pool” of follicles that will be induced to enter growth and developmental changes that change them into pre-ovulatory follicles, ready to be released during ovulation. The process of development from a primordial follicle to a pre-ovulatory follicle is called folliculogenesis.

<span class="mw-page-title-main">Artificial ovary</span>

An artificial ovary is a potential fertility preservation treatment that aims to mimic the function of the natural ovary.

<span class="mw-page-title-main">Ovarian stem cell</span>

Ovarian stem cells are oocytes formed in ovarian follicle before birth in female mammals. They do not form post-natally, and are depleted throughout reproductive life. In humans it is estimated that 500,000–1,000,000 primordial follicles are present at birth, decreasing rapidly with age until roughly age 51 when ovulation stops, resulting in menopause. The origin of these oocytes remains under discussion. The publication of a study in 2004 proposing germ cell renewal in adult mice sparked a debate on the possibility of stem cells in the postnatal ovary. An increasing number of studies suggest that stem cells exist within the mammalian ovary and can be manipulated in vitro to produce oocytes, but whether such ovarian stem cells have the potential to differentiate into oocytes remains uncertain.

Oocytes are immature egg cells that develop to maturity within a follicle in the ovary. Oocyte abnormalities can occur due to several factors, including premature ovarian insufficiency (POI), other maturation abnormalities, maternal ageing, and mitochondrial abnormalities.

References

  1. 1 2 3 ENSG00000285328 GRCh38: Ensembl release 89: ENSG00000106410, ENSG00000285328 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029736 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: NOBOX oogenesis homeobox".
  6. 1 2 3 4 5 Suzumori N, Yan C, Matzuk MM, Rajkovic A (February 2002). "Nobox is a homeobox-encoding gene preferentially expressed in primordial and growing oocytes". Mechanisms of Development. 111 (1–2): 137–41. doi:10.1016/S0925-4773(01)00620-7. PMID   11804785. S2CID   7205659.
  7. 1 2 Huntriss J, Hinkins M, Picton HM (May 2006). "cDNA cloning and expression of the human NOBOX gene in oocytes and ovarian follicles". Molecular Human Reproduction. 12 (5): 283–9. doi:10.1093/molehr/gal035. PMID   16597639.
  8. 1 2 3 4 5 Rajkovic A, Pangas SA, Ballow D, Suzumori N, Matzuk MM (August 2004). "NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression". Science. 305 (5687): 1157–9. Bibcode:2004Sci...305.1157R. doi:10.1126/science.1099755. PMID   15326356. S2CID   26646489.
  9. ↑ Kay BK, Williamson MP, Sudol M (February 2000). "The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains". FASEB Journal. 14 (2): 231–41. doi:10.1096/fasebj.14.2.231. PMID   10657980. S2CID   10475561.
  10. 1 2 3 4 Choi Y, Rajkovic A (November 2006). "Characterization of NOBOX DNA binding specificity and its regulation of Gdf9 and Pou5f1 promoters". The Journal of Biological Chemistry. 281 (47): 35747–56. doi: 10.1074/jbc.M604008200 . PMID   16997917.
  11. 1 2 Bouilly J, Bachelot A, Broutin I, Touraine P, Binart N (October 2011). "Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort". Human Mutation. 32 (10): 1108–13. doi: 10.1002/humu.21543 . PMID   21837770. S2CID   30861702.
  12. ↑ Laughon A (December 1991). "DNA binding specificity of homeodomains". Biochemistry. 30 (48): 11357–67. doi:10.1021/bi00112a001. PMID   1742275.
  13. ↑ Fraenkel E, Pabo CO (August 1998). "Comparison of X-ray and NMR structures for the Antennapedia homeodomain-DNA complex". Nature Structural Biology. 5 (8): 692–7. doi:10.1038/1382. PMID   9699632. S2CID   24233895.
  14. ↑ Kissinger CR, Liu BS, Martin-Blanco E, Kornberg TB, Pabo CO (November 1990). "Crystal structure of an engrailed homeodomain-DNA complex at 2.8 A resolution: a framework for understanding homeodomain-DNA interactions". Cell. 63 (3): 579–90. doi: 10.1016/0092-8674(90)90453-l . PMID   1977522. S2CID   1678791.
  15. 1 2 Choi Y, Qin Y, Berger MF, Ballow DJ, Bulyk ML, Rajkovic A (August 2007). "Microarray analyses of newborn mouse ovaries lacking Nobox". Biology of Reproduction. 77 (2): 312–9. doi: 10.1095/biolreprod.107.060459 . PMID   17494914.
  16. 1 2 Li L, Wang B, Zhang W, Chen B, Luo M, Wang J, Wang X, Cao Y, Kee K (January 2017). "A homozygous NOBOX truncating variant causes defective transcriptional activation and leads to primary ovarian insufficiency". Human Reproduction. 32 (1): 248–255. doi: 10.1093/humrep/dew271 . PMID   27836978.
  17. 1 2 Qin Y, Choi Y, Zhao H, Simpson JL, Chen ZJ, Rajkovic A (September 2007). "NOBOX homeobox mutation causes premature ovarian failure". American Journal of Human Genetics. 81 (3): 576–81. doi:10.1086/519496. PMC   1950834 . PMID   17701902.
  18. ↑ Vegetti W, Grazia Tibiletti M, Testa G, Alagna F, Castoldi E, Taborelli M, Motta T, Bolis PF, Dalprà L, Crosignani PG (July 1998). "Inheritance in idiopathic premature ovarian failure: analysis of 71 cases". Human Reproduction. 13 (7): 1796–800. doi: 10.1093/humrep/13.7.1796 . PMID   9740426.
  19. 1 2 Coulam CB, Adamson SC, Annegers JF (April 1986). "Incidence of premature ovarian failure". Obstetrics and Gynecology. 67 (4): 604–6. PMID   3960433.
  20. ↑ De Vos M, Devroey P, Fauser BC (September 2010). "Primary ovarian insufficiency". Lancet. 376 (9744): 911–21. doi:10.1016/S0140-6736(10)60355-8. PMID   20708256. S2CID   19404756.
  21. ↑ Bouilly J, Roucher-Boulez F, Gompel A, Bry-Gauillard H, Azibi K, Beldjord C, Dodé C, Bouligand J, Mantel AG, Hécart AC, Delemer B, Young J, Binart N (March 2015). "New NOBOX mutations identified in a large cohort of women with primary ovarian insufficiency decrease KIT-L expression". The Journal of Clinical Endocrinology and Metabolism. 100 (3): 994–1001. doi: 10.1210/jc.2014-2761 . PMID   25514101.
  22. ↑ Bouali N, Francou B, Bouligand J, Lakhal B, Malek I, Kammoun M, Warszawski J, Mougou S, Saad A, Guiochon-Mantel A (May 2016). "NOBOX is a strong autosomal candidate gene in Tunisian patients with primary ovarian insufficiency". Clinical Genetics. 89 (5): 608–13. doi:10.1111/cge.12750. PMID   26848058. S2CID   25656158.
  23. ↑ Qin Y, Shi Y, Zhao Y, Carson SA, Simpson JL, Chen ZJ (April 2009). "Mutation analysis of NOBOX homeodomain in Chinese women with premature ovarian failure". Fertility and Sterility. 91 (4 Suppl): 1507–9. doi: 10.1016/j.fertnstert.2008.08.020 . PMID   18930203.
  24. ↑ Zhao XX, Suzumori N, Yamaguchi M, Suzumori K (June 2005). "Mutational analysis of the homeobox region of the human NOBOX gene in Japanese women who exhibit premature ovarian failure". Fertility and Sterility. 83 (6): 1843–4. doi: 10.1016/j.fertnstert.2004.12.031 . PMID   15950662.
  25. ↑ Bayne RA, Kinnell HL, Coutts SM, He J, Childs AJ, Anderson RA (2015-03-19). "GDF9 is transiently expressed in oocytes before follicle formation in the human fetal ovary and is regulated by a novel NOBOX transcript". PLOS ONE. 10 (3): e0119819. Bibcode:2015PLoSO..1019819B. doi: 10.1371/journal.pone.0119819 . PMC   4366263 . PMID   25790371.
  26. ↑ Bouilly J, Veitia RA, Binart N (April 2014). "NOBOX is a key FOXL2 partner involved in ovarian folliculogenesis". Journal of Molecular Cell Biology. 6 (2): 175–7. doi:10.1093/jmcb/mju006. PMID   24620032. S2CID   16608843.
  27. ↑ Bouilly J, Beau I, Barraud S, Bernard V, Delemer B, Young J, Binart N (July 2017). "R-spondin2, a novel target of NOBOX: identification of variants in a cohort of women with primary ovarian insufficiency". Journal of Ovarian Research. 10 (1): 51. doi: 10.1186/s13048-017-0345-0 . PMC   5526297 . PMID   28743298.

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