Retinoblastoma gene or the Rb gene is a tumour suppressor gene. This means that its normal function is to inhibit the cell cycle and prevent the cell from replicating further. Basically it puts a brake on the cells replication. 

Let's recap the cell cycle to better understand which phase of the cycle, the Rb gene aims to attack. 

• It begins with The G1 phase, where the cell undergoes metabolic changes to prepare itself for division. 
• Then comes the S phase, where the DNA is replicated.
• Next is the G2 phase, which undergoes further metabolic changes for cell mitosis.
• Lastly is the M phase, when mitosis (nuclear division) and cytokinesis (cellular division) takes place.

Check out our article on cell cycle to understand the details of the cell cycle and its regulation. 

The Rb gene comes Into play at the G1 phase and makes sure the cell doesn't progress to the S phase so DNA replication and further propagation of cells don’t occur. It’s important to note here, that we study about this gene because it’s function helps us to regulate the rate of cell growth by stopping DNA replication in the S phase.

The dysfunction of this cell obviously causes uncontrollable growth of cells, which leads to the formation of tumours. As, the Rb gene is present in maximum concentrations in the eye, the most common neoplasm associated with Rb mutation is Retinoblastoma. The second most common neoplasm associated with Rb mutation is osteosarcoma. 

What does mutation of a Rb gene mean? The Rb gene is located on the long arm of the 13th chromosome. Rb gene has two domains, Domain A, which acts like a receptor for the binding of a transcriptional factor called E2F and Domain B. The Rb gene remains activated in the dephosphorylated state where it can bind to E2F. Dephosphorylation of Rb gene is done by an enzyme called Protein phosphatase 1. When it should be inactivated in the G1 phase of the call cycle, so DNA replication in the S phase is inhibited, it is phosphorylated to a state called PRb. This phosphorylation is done by cyclins and some enzymes called cyclin dependent kinases. PRb is not able to bind with E2F. Thus when there is a defect in the phosphorylation of the Rb gene, it remains in it’s dephosphorylated form, which can bind to E2F and promote DNA replication continuously, resulting in uncontrollable cell growth which leads to the growth of a tumour like explained above.

Retinoblastoma is a rare neoplasm of the eye that usually occurs in children under the age of five. It affects the retina which  is responsible for sensing light and colour. The cells in the retina are not sloughed off and replaced like they normally should be because of uncontrolled proliferation. The first sign elicited in children suffering from retinoblastoma is whiteness in the eye, also called, Leukocoria. In addition, when a light is shone on the eye, there is sheen seen in the pupil which is commonly seen in feline animals, hence this is also known as Cat’s Eye. The other common symptoms include, strabismus or crossed eyes, redness of the white part of the eye called the sclera and swelling of eyelids.

The interesting thing about the mutations of the Rb gene is that it follows Knudson’s Two Hit hypothesis. The principle of this hypothesis is that both the alleles of the Rb gene must be damaged in order for the function to be impaired to such an extent that it causes a neoplasm.

As a result, there are two genetic variations of Retinoblastoma. The bilateral form is when it affects both the eyes. It’s also called the familial form because it is passed on in the family to some extent. Here one mutated allele is passed down in the family. Which means the gene already has one hit. If the second allele gets mutated by environmental factors, then the function of the gene will be completely lost leading to a neoplasm. This form is more common and more dangerous as it only requires a single hit. It works by the principle of linear kinetics. 

The other form is called unilateral as it affects only one eye. It's also called sporadic as this cancer occurs in irregular cases. In this case, the gene is completely normal and both alleles are functioning normally at birth. Environmental factors must damage both alleles for the tumor to manifest. This form works by the principle of polynomial kinetics.

So basically, Retinoblastoma is the result of the dysfunction of a tumour suppressor gene, that leads to the growth of tumours, that establish a neoplasm of the eye. The  understanding of the functions of important genes like the Rb gene and the p53 gene gives us an insight into the development of neoplasms and equip us with the tools to try and stop them.