NOBOX

Key takeaways

NOBOX belongs to biology; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect NOBOX to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of NOBOX from memory before moving on to harder problems.

Reference excerpt

Homeobox protein NOBOX, also known as newborn ovary homeobox protein, is a protein that in humans is encoded by the NOBOX gene. 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.

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

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

Mutations and clinical significance A mutation in the NOBOX gene is associated with premature ovarian failure (POF), also known as premature ovarian insufficiency (POI). 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). It affects ≈1% of women below 40 years old. A study conducted on 96 white women with POF revealed one case of heterozygous mutation in the NOBOX homeodomain, p.Arg355His, in one patient. 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%. 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. The POF syndrome is a highly heterogenous clinical disorder but a recent study showed the first homozygous mutation associated with NOBOX loss-of-function. 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.

Interactions GDF9 POU5F1 DNMT10 FOXL2 FIGLA RSPO2 DMRT1

References

Illustrations

Worked examples

Example 1 — a first encounter with NOBOX

Start with the simplest possible case. Write down what NOBOX claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to NOBOX before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about NOBOX ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of NOBOX

In research: NOBOX appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses NOBOX in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: NOBOX is common in secondary-school and first-year university syllabi. It links to neighbouring topics Genes on human chromosome 7, Transcription factors, so understanding it makes those chapters shorter.
In everyday life: Look for NOBOX outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study NOBOX in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what NOBOX means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain NOBOX out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is NOBOX in simple terms?

Homeobox protein NOBOX, also known as newborn ovary homeobox protein, is a protein that in humans is encoded by the NOBOX gene. The official symbol (NOBOX) and the official full name (NOBOX oogenesis homeobox) are maintained by the HGNC.

Why does NOBOX matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study NOBOX?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on NOBOX.