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{{Infobox_gene}}
{{Infobox_gene}}
'''Homeobox protein NOBOX''', also known as '''newborn ovary homeobox protein''', is a [[protein]] that in humans is encoded by the ''NOBOX'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: NOBOX oogenesis homeobox| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=135935| accessdate = }}</ref><ref name="pmid11804785">{{cite journal | vauthors = Suzumori N, Yan C, Matzuk MM, Rajkovic A | title = Nobox is a homeobox-encoding gene preferentially expressed in primordial and growing oocytes | journal = Mechanisms of Development | volume = 111 | issue = 1-2 | pages = 137–41 | date = Feb 2002 | pmid = 11804785 | doi = 10.1016/S0925-4773(01)00620-7 }}</ref><ref name="pmid16597639">{{cite journal | vauthors = Huntriss J, Hinkins M, Picton HM | title = cDNA cloning and expression of the human NOBOX gene in oocytes and ovarian follicles | journal = Molecular Human Reproduction | volume = 12 | issue = 5 | pages = 283–9 | date = May 2006 | pmid = 16597639 | doi = 10.1093/molehr/gal035 }}</ref>
'''Homeobox protein NOBOX''', also known as '''newborn ovary homeobox protein''', is a [[protein]] that in humans is encoded by the ''NOBOX'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: NOBOX oogenesis homeobox| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=135935| access-date = }}</ref><ref name="pmid11804785">{{cite journal | vauthors = Suzumori N, Yan C, Matzuk MM, Rajkovic A | title = Nobox is a homeobox-encoding gene preferentially expressed in primordial and growing oocytes | journal = Mechanisms of Development | volume = 111 | issue = 1-2 | pages = 137–41 | date = February 2002 | pmid = 11804785 | doi = 10.1016/S0925-4773(01)00620-7 }}</ref><ref name="pmid16597639">{{cite journal | vauthors = Huntriss J, Hinkins M, Picton HM | title = cDNA cloning and expression of the human NOBOX gene in oocytes and ovarian follicles | journal = Molecular Human Reproduction | volume = 12 | issue = 5 | pages = 283–9 | date = May 2006 | pmid = 16597639 | doi = 10.1093/molehr/gal035 }}</ref> 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 [[Sequence homology|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 [[oocyte]]s decrease in its absence which lead to [[infertility]].<ref name=":2" />
 
== 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.<ref name="pmid11804785" /> 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.<ref name="pmid11804785" /> It has a proline rich C terminus and contains putative SH3 and WW domains.<ref>{{cite journal | vauthors = Kay BK, Williamson MP, Sudol M | title = The importance of being proline: the interaction of proline-rich motifs in signaling proteins with their cognate domains | journal = FASEB Journal | volume = 14 | issue = 2 | pages = 231–41 | date = February 2000 | pmid = 10657980 }}</ref> This C terminus is believed to be critical in its transcriptional activities when bound to oocyte-specific genes.<ref name=":0">{{cite journal | vauthors = Choi Y, Rajkovic A | title = Characterization of NOBOX DNA binding specificity and its regulation of Gdf9 and Pou5f1 promoters | journal = The Journal of Biological Chemistry | volume = 281 | issue = 47 | pages = 35747–56 | date = November 2006 | pmid = 16997917 | doi = 10.1074/jbc.M604008200 }}</ref> 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.<ref name=":3" /> It contains an asparagine residue at position 51 which is important for its interactions with DNA base pairs.<ref>{{cite journal|vauthors=Laughon A|date=December 1991|title=DNA binding specificity of homeodomains|journal=Biochemistry|language=EN|volume=30|issue=48|pages=11357–67|doi=10.1021/bi00112a001|pmid=1742275}}</ref><ref>{{cite journal | vauthors = Fraenkel E, Pabo CO | title = Comparison of X-ray and NMR structures for the Antennapedia homeodomain-DNA complex | journal = Nature Structural Biology | volume = 5 | issue = 8 | pages = 692–7 | date = August 1998 | pmid = 9699632 | doi = 10.1038/1382 }}</ref><ref>{{cite journal | vauthors = Kissinger CR, Liu BS, Martin-Blanco E, Kornberg TB, Pabo CO | title = Crystal structure of an engrailed homeodomain-DNA complex at 2.8 A resolution: a framework for understanding homeodomain-DNA interactions | journal = Cell | volume = 63 | issue = 3 | pages = 579–90 | date = November 1990 | pmid = 1977522 }}</ref>


== Function ==
== Function ==


NOBOX is a [[homeobox]] gene that is preferentially expressed in [[oocyte]]s. In mice, it is essential for [[folliculogenesis]] and regulation of oocyte-specific genes.<ref name="pmid16597639"/>
''NOBOX'' is a [[homeobox]] gene that is preferentially expressed in oocytes. In mice, it is essential for folliculogenesis and regulation of oocyte-specific genes.<ref name="pmid16597639"/> 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'.<ref name=":0" /> 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.<ref name=":1">{{cite journal | vauthors = Choi Y, Qin Y, Berger MF, Ballow DJ, Bulyk ML, Rajkovic A | title = Microarray analyses of newborn mouse ovaries lacking Nobox | journal = Biology of Reproduction | volume = 77 | issue = 2 | pages = 312–9 | date = August 2007 | pmid = 17494914 | doi = 10.1095/biolreprod.107.060459 }}</ref> 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|Dmrt1]]''.<ref name=":1" /> Its deficiency can cause rapid loss of postnatal oocytes and during its absence in female mice, follicles are replaced by fibrous tissue.<ref name="pmid11804785" /> Recently, a new role of NOBOX in controlling the [[G2-M DNA damage checkpoint|G2/M]] arrest was discovered.<ref name=":4" />


== Clinical significance ==
== Mutations and clinical significance ==


A mutation in the NOBOX gene is associated with [[premature ovarian failure]].<ref name="pmid17701902">{{cite journal | vauthors = Qin Y, Choi Y, Zhao H, Simpson JL, Chen ZJ, Rajkovic A | title = NOBOX homeobox mutation causes premature ovarian failure | journal = American Journal of Human Genetics | volume = 81 | issue = 3 | pages = 576–81 | date = Sep 2007 | pmid = 17701902 | pmc = 1950834 | doi = 10.1086/519496 }}</ref>
A mutation in the NOBOX gene is associated with [[premature ovarian failure|premature ovarian failure (POF),]] also known as premature ovarian insufficiency (POI).<ref name="pmid17701902">{{cite journal | vauthors = Qin Y, Choi Y, Zhao H, Simpson JL, Chen ZJ, Rajkovic A | title = NOBOX homeobox mutation causes premature ovarian failure | journal = American Journal of Human Genetics | volume = 81 | issue = 3 | pages = 576–81 | date = September 2007 | pmid = 17701902 | pmc = 1950834 | doi = 10.1086/519496 }}</ref> 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).<ref>{{cite journal | vauthors = Vegetti W, Grazia Tibiletti M, Testa G, Alagna F, Castoldi E, Taborelli M, Motta T, Bolis PF, Dalprà L, Crosignani PG | title = Inheritance in idiopathic premature ovarian failure: analysis of 71 cases | journal = Human Reproduction | volume = 13 | issue = 7 | pages = 1796–800 | date = July 1998 | pmid = 9740426 }}</ref><ref name=":5">{{cite journal | vauthors = Coulam CB, Adamson SC, Annegers JF | title = Incidence of premature ovarian failure | journal = Obstetrics and Gynecology | volume = 67 | issue = 4 | pages = 604–6 | date = April 1986 | pmid = 3960433 }}</ref> It affects ≈1% of women below 40 years old.<ref>{{cite journal | vauthors = De Vos M, Devroey P, Fauser BC | title = Primary ovarian insufficiency | journal = Lancet | volume = 376 | issue = 9744 | pages = 911–21 | date = September 2010 | pmid = 20708256 | doi = 10.1016/S0140-6736(10)60355-8 }}</ref> A study conducted on 96 white women with POF revealed one case of [[Zygosity|heterozygous]] mutation in the NOBOX homeodomain, p.Arg355His, in one patient.<ref name="pmid17701902" /> 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%.<ref name=":3">{{cite journal | vauthors = Bouilly J, Bachelot A, Broutin I, Touraine P, Binart N | title = Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort | journal = Human Mutation | volume = 32 | issue = 10 | pages = 1108–13 | date = October 2011 | pmid = 21837770 | doi = 10.1002/humu.21543 }}</ref><ref>{{cite journal | vauthors = 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 | title = New NOBOX mutations identified in a large cohort of women with primary ovarian insufficiency decrease KIT-L expression | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 100 | issue = 3 | pages = 994–1001 | date = March 2015 | pmid = 25514101 | doi = 10.1210/jc.2014-2761 }}</ref><ref>{{cite journal | vauthors = Bouali N, Francou B, Bouligand J, Lakhal B, Malek I, Kammoun M, Warszawski J, Mougou S, Saad A, Guiochon-Mantel A | title = NOBOX is a strong autosomal candidate gene in Tunisian patients with primary ovarian insufficiency | journal = Clinical Genetics | volume = 89 | issue = 5 | pages = 608–13 | date = May 2016 | pmid = 26848058 | doi = 10.1111/cge.12750 }}</ref> 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.<ref>{{cite journal | vauthors = Qin Y, Shi Y, Zhao Y, Carson SA, Simpson JL, Chen ZJ | title = Mutation analysis of NOBOX homeodomain in Chinese women with premature ovarian failure | journal = Fertility and Sterility | volume = 91 | issue = 4 Suppl | pages = 1507–9 | date = April 2009 | pmid = 18930203 | doi = 10.1016/j.fertnstert.2008.08.020 }}</ref><ref>{{cite journal | vauthors = Zhao XX, Suzumori N, Yamaguchi M, Suzumori K | title = Mutational analysis of the homeobox region of the human NOBOX gene in Japanese women who exhibit premature ovarian failure | language = English | journal = Fertility and Sterility | volume = 83 | issue = 6 | pages = 1843–4 | date = June 2005 | pmid = 15950662 | doi = 10.1016/j.fertnstert.2004.12.031 }}</ref>
 
The POF syndrome is a highly heterogenous clinical disorder but a recent study showed the first [[Zygosity|homozygous]] mutation associated with NOBOX loss-of-function.<ref name=":4">{{cite journal | vauthors = Li L, Wang B, Zhang W, Chen B, Luo M, Wang J, Wang X, Cao Y, Kee K | title = A homozygous NOBOX truncating variant causes defective transcriptional activation and leads to primary ovarian insufficiency | journal = Human Reproduction | volume = 32 | issue = 1 | pages = 248–255 | date = January 2017 | pmid = 27836978 | doi = 10.1093/humrep/dew271 }}</ref> 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 [[Growth differentiation factor-9|GDF9]], a well-known target of NOBOX, which led to the lost ability of NOBOX to induce [[G2-M DNA damage checkpoint|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.<ref name=":2" />
 
== Interactions ==
 
# [[Bone morphogenetic protein 15|GDF9]]<ref name=":0" /><ref>{{cite journal | vauthors = Bayne RA, Kinnell HL, Coutts SM, He J, Childs AJ, Anderson RA | title = GDF9 is transiently expressed in oocytes before follicle formation in the human fetal ovary and is regulated by a novel NOBOX transcript | journal = PLOS One | volume = 10 | issue = 3 | pages = e0119819 | date = 2015-03-19 | pmid = 25790371 | pmc = 4366263 | doi = 10.1371/journal.pone.0119819 }}</ref>
# [[Oct-4|POU5F1]]<ref name="pmid11804785" /><ref name=":0" /><ref name=":2">{{cite journal | vauthors = Rajkovic A, Pangas SA, Ballow D, Suzumori N, Matzuk MM | title = NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression | journal = Science | volume = 305 | issue = 5687 | pages = 1157–9 | date = August 2004 | pmid = 15326356 | doi = 10.1126/science.1099755 }}</ref>
# [[DNMT1|DNMT10]]<ref name=":2" />
# [[Forkhead box L2|FOXL2]]<ref>{{cite journal | vauthors = Bouilly J, Veitia RA, Binart N | title = NOBOX is a key FOXL2 partner involved in ovarian folliculogenesis | journal = Journal of Molecular Cell Biology | volume = 6 | issue = 2 | pages = 175–7 | date = April 2014 | pmid = 24620032 | doi = 10.1093/jmcb/mju006 }}</ref>
#[[FIGLA]]<ref name=":2" />
#[[R-spondin 2|RSPO2]]<ref>{{cite journal | vauthors = Bouilly J, Beau I, Barraud S, Bernard V, Delemer B, Young J, Binart N | title = R-spondin2, a novel target of NOBOX: identification of variants in a cohort of women with primary ovarian insufficiency | journal = Journal of Ovarian Research | volume = 10 | issue = 1 | pages = 51 | date = July 2017 | pmid = 28743298 | pmc = 5526297 | doi = 10.1186/s13048-017-0345-0 }}</ref>
#[[DMRT1]]<ref name=":5" />


== References ==
== References ==
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== Further reading ==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
* {{cite journal | vauthors = Rovescalli AC, Asoh S, Nirenberg M | title = Cloning and characterization of four murine homeobox genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 20 | pages = 10691–6 | date = Oct 1996 | pmid = 8855241 | pmc = 38216 | doi = 10.1073/pnas.93.20.10691 }}
* {{cite journal | vauthors = Rovescalli AC, Asoh S, Nirenberg M | title = Cloning and characterization of four murine homeobox genes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 20 | pages = 10691–6 | date = October 1996 | pmid = 8855241 | pmc = 38216 | doi = 10.1073/pnas.93.20.10691 }}
* {{cite journal | vauthors = Qin Y, Choi Y, Zhao H, Simpson JL, Chen ZJ, Rajkovic A | title = NOBOX homeobox mutation causes premature ovarian failure | journal = American Journal of Human Genetics | volume = 81 | issue = 3 | pages = 576–81 | date = Sep 2007 | pmid = 17701902 | pmc = 1950834 | doi = 10.1086/519496 }}
* {{cite journal | vauthors = Qin Y, Choi Y, Zhao H, Simpson JL, Chen ZJ, Rajkovic A | title = NOBOX homeobox mutation causes premature ovarian failure | journal = American Journal of Human Genetics | volume = 81 | issue = 3 | pages = 576–81 | date = September 2007 | pmid = 17701902 | pmc = 1950834 | doi = 10.1086/519496 }}
* {{cite journal | vauthors = Brauner R, Bashamboo A, Rouget S, Goulet M, Philibert P, Sarda-Thibault H, Trivin C, Misrahi M, Sultan C, McElreavey K | title = Clinical, biological and genetic analysis of prepubertal isolated ovarian cyst in 11 girls | journal = PLoS One | volume = 5 | issue = 6 | pages = e11282 | year = 2010 | pmid = 20593028 | pmc = 2892512 | doi = 10.1371/journal.pone.0011282 }}
* {{cite journal | vauthors = Brauner R, Bashamboo A, Rouget S, Goulet M, Philibert P, Sarda-Thibault H, Trivin C, Misrahi M, Sultan C, McElreavey K | title = Clinical, biological and genetic analysis of prepubertal isolated ovarian cyst in 11 girls | journal = PLOS One | volume = 5 | issue = 6 | pages = e11282 | date = June 2010 | pmid = 20593028 | pmc = 2892512 | doi = 10.1371/journal.pone.0011282 }}
* {{cite journal | vauthors = Zhao XX, Suzumori N, Yamaguchi M, Suzumori K | title = Mutational analysis of the homeobox region of the human NOBOX gene in Japanese women who exhibit premature ovarian failure | journal = Fertility and Sterility | volume = 83 | issue = 6 | pages = 1843–4 | date = Jun 2005 | pmid = 15950662 | doi = 10.1016/j.fertnstert.2004.12.031 }}
* {{cite journal | vauthors = Zhao XX, Suzumori N, Yamaguchi M, Suzumori K | title = Mutational analysis of the homeobox region of the human NOBOX gene in Japanese women who exhibit premature ovarian failure | journal = Fertility and Sterility | volume = 83 | issue = 6 | pages = 1843–4 | date = June 2005 | pmid = 15950662 | doi = 10.1016/j.fertnstert.2004.12.031 }}
* {{cite journal | vauthors = Oldenburg RA, van Dooren MF, de Graaf B, Simons E, Govaerts L, Swagemakers S, Verkerk JM, Oostra BA, Bertoli-Avella AM | title = A genome-wide linkage scan in a Dutch family identifies a premature ovarian failure susceptibility locus | journal = Human Reproduction | volume = 23 | issue = 12 | pages = 2835–41 | date = Dec 2008 | pmid = 18689850 | doi = 10.1093/humrep/den278 }}
* {{cite journal | vauthors = Oldenburg RA, van Dooren MF, de Graaf B, Simons E, Govaerts L, Swagemakers S, Verkerk JM, Oostra BA, Bertoli-Avella AM | title = A genome-wide linkage scan in a Dutch family identifies a premature ovarian failure susceptibility locus | journal = Human Reproduction | volume = 23 | issue = 12 | pages = 2835–41 | date = December 2008 | pmid = 18689850 | doi = 10.1093/humrep/den278 }}
* {{cite journal | vauthors = van Dooren MF, Bertoli-Avellab AM, Oldenburg RA | title = Premature ovarian failure and gene polymorphisms | journal = Current Opinion in Obstetrics and Gynecology | volume = 21 | issue = 4 | pages = 313–7 | date = Aug 2009 | pmid = 19610175 | doi = }}
* {{cite journal | vauthors = van Dooren MF, Bertoli-Avellab AM, Oldenburg RA | title = Premature ovarian failure and gene polymorphisms | journal = Current Opinion in Obstetrics & Gynecology | volume = 21 | issue = 4 | pages = 313–7 | date = August 2009 | pmid = 19610175 | doi = 10.1097/gco.0b013e32832e0813 }}
* {{cite journal | vauthors = Rajkovic A, Pangas SA, Ballow D, Suzumori N, Matzuk MM | title = NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression | journal = Science | volume = 305 | issue = 5687 | pages = 1157–9 | date = Aug 2004 | pmid = 15326356 | doi = 10.1126/science.1099755 }}
* {{cite journal | vauthors = Rajkovic A, Pangas SA, Ballow D, Suzumori N, Matzuk MM | title = NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression | journal = Science | volume = 305 | issue = 5687 | pages = 1157–9 | date = August 2004 | pmid = 15326356 | doi = 10.1126/science.1099755 }}
* {{cite journal | vauthors = Rossi E, Verri AP, Patricelli MG, Destefani V, Ricca I, Vetro A, Ciccone R, Giorda R, Toniolo D, Maraschio P, Zuffardi O | title = A 12Mb deletion at 7q33-q35 associated with autism spectrum disorders and primary amenorrhea | journal = European Journal of Medical Genetics | volume = 51 | issue = 6 | pages = 631–8 | year = 2008 | pmid = 18675947 | doi = 10.1016/j.ejmg.2008.06.010 }}
* {{cite journal | vauthors = Rossi E, Verri AP, Patricelli MG, Destefani V, Ricca I, Vetro A, Ciccone R, Giorda R, Toniolo D, Maraschio P, Zuffardi O | title = A 12Mb deletion at 7q33-q35 associated with autism spectrum disorders and primary amenorrhea | journal = European Journal of Medical Genetics | volume = 51 | issue = 6 | pages = 631–8 | year = 2008 | pmid = 18675947 | doi = 10.1016/j.ejmg.2008.06.010 }}
* {{cite journal | vauthors = Qin Y, Shi Y, Zhao Y, Carson SA, Simpson JL, Chen ZJ | title = Mutation analysis of NOBOX homeodomain in Chinese women with premature ovarian failure | journal = Fertility and Sterility | volume = 91 | issue = 4 Suppl | pages = 1507–9 | date = Apr 2009 | pmid = 18930203 | doi = 10.1016/j.fertnstert.2008.08.020 }}
* {{cite journal | vauthors = Qin Y, Shi Y, Zhao Y, Carson SA, Simpson JL, Chen ZJ | title = Mutation analysis of NOBOX homeodomain in Chinese women with premature ovarian failure | journal = Fertility and Sterility | volume = 91 | issue = 4 Suppl | pages = 1507–9 | date = April 2009 | pmid = 18930203 | doi = 10.1016/j.fertnstert.2008.08.020 }}
{{refend}}
{{refend}}


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[[Category:Transcription factors]]
[[Category:Transcription factors]]
{{gene-7-stub}}

Latest revision as of 18:27, 27 November 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

Homeobox protein NOBOX, also known as newborn ovary homeobox protein, is a protein that in humans is encoded by the NOBOX gene.[1][2][3] 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.[4]

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.[2] 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.[2] It has a proline rich C terminus and contains putative SH3 and WW domains.[5] This C terminus is believed to be critical in its transcriptional activities when bound to oocyte-specific genes.[6] 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.[7] It contains an asparagine residue at position 51 which is important for its interactions with DNA base pairs.[8][9][10]

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.[3] 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'.[6] 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.[11] 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.[11] Its deficiency can cause rapid loss of postnatal oocytes and during its absence in female mice, follicles are replaced by fibrous tissue.[2] Recently, a new role of NOBOX in controlling the G2/M arrest was discovered.[12]

Mutations and clinical significance

A mutation in the NOBOX gene is associated with premature ovarian failure (POF), also known as premature ovarian insufficiency (POI).[13] 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).[14][15] It affects ≈1% of women below 40 years old.[16] A study conducted on 96 white women with POF revealed one case of heterozygous mutation in the NOBOX homeodomain, p.Arg355His, in one patient.[13] 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%.[7][17][18] 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.[19][20]

The POF syndrome is a highly heterogenous clinical disorder but a recent study showed the first homozygous mutation associated with NOBOX loss-of-function.[12] 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.[4]

Interactions

  1. GDF9[6][21]
  2. POU5F1[2][6][4]
  3. DNMT10[4]
  4. FOXL2[22]
  5. FIGLA[4]
  6. RSPO2[23]
  7. DMRT1[15]

References

  1. ↑ "Entrez Gene: NOBOX oogenesis homeobox".
  2. ↑ 2.0 2.1 2.2 2.3 2.4 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.
  3. ↑ 3.0 3.1 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.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 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. doi:10.1126/science.1099755. PMID 15326356.
  5. ↑ 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. PMID 10657980.
  6. ↑ 6.0 6.1 6.2 6.3 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.
  7. ↑ 7.0 7.1 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.
  8. ↑ Laughon A (December 1991). "DNA binding specificity of homeodomains". Biochemistry. 30 (48): 11357–67. doi:10.1021/bi00112a001. PMID 1742275.
  9. ↑ 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.
  10. ↑ 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. PMID 1977522.
  11. ↑ 11.0 11.1 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.
  12. ↑ 12.0 12.1 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.
  13. ↑ 13.0 13.1 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.
  14. ↑ 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. PMID 9740426.
  15. ↑ 15.0 15.1 Coulam CB, Adamson SC, Annegers JF (April 1986). "Incidence of premature ovarian failure". Obstetrics and Gynecology. 67 (4): 604–6. PMID 3960433.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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. doi:10.1371/journal.pone.0119819. PMC 4366263. PMID 25790371.
  22. ↑ 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.
  23. ↑ 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.

Further reading

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