Homeobox protein NOBOX, also known asnewborn ovary homeobox protein, is aprotein that in humans is encoded by theNOBOXgene.[5][6][7] The official symbol (NOBOX) and the official full name (NOBOX oogenesis homeobox) are maintained by theHGNC. TheNOBOX gene is conserved in chimpanzee, Rhesus monkey, cow, mouse, and rat. There are 175 organisms that haveorthologs with human geneNOBOX. It is capable of regulating other genes that are important in the development of follicles. Follicles do not develop andoocytes decrease in its absence which lead toinfertility.[8]
NOBOX is anin silico subtraction discovery when Suzumoriet al. searched for novel genes involved in early mammalianfolliculogenesis 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.
The humanNOBOX 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 containshomeodomain. 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]
NOBOX is ahomeobox 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 ofNOBOX 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 byNOBOX in newborn ovaries. NOBOX also plays an important role in the suppression of male-determining genes such asDmrt1.[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 theG2/M arrest was discovered.[16]
A mutation in the NOBOX gene is associated withpremature 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 elevatedfollicle-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 ofheterozygous 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 thatNOBOX 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 firsthomozygous 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 theNOBOX gene. This truncated variant caused a defective transcriptional activation ofGDF9, a well-known target of NOBOX, which led to the lost ability of NOBOX to induceG2/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]
^abcdeSuzumori 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.PMID11804785.S2CID7205659.
^abHuntriss 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.PMID16597639.
^Laughon A (December 1991). "DNA binding specificity of homeodomains".Biochemistry.30 (48):11357–67.doi:10.1021/bi00112a001.PMID1742275.
^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.PMID9699632.S2CID24233895.
^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.PMID26848058.S2CID25656158.
Rossi E, Verri AP, Patricelli MG, Destefani V, Ricca I, Vetro A, Ciccone R, Giorda R, Toniolo D, Maraschio P, Zuffardi O (2008). "A 12Mb deletion at 7q33-q35 associated with autism spectrum disorders and primary amenorrhea".European Journal of Medical Genetics.51 (6):631–8.doi:10.1016/j.ejmg.2008.06.010.PMID18675947.
