Retinoblastoma: Mutation of Rb-1 Protein
Sponsored by Missouri Western State University Sponsored by a grant from the National Science Foundation DUE-97-51113
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KELLY, K. L. (2000). Retinoblastoma: Mutation of Rb-1 Protein. National Undergraduate Research Clearinghouse, 3. Available online at Retrieved April 25, 2017 .

Retinoblastoma: Mutation of Rb-1 Protein

Sponsored by: TODD ECKDAHL (
Retinoblatoma is a serious form of cancer that generally affects children. There are many symptoms that help in catching the disease early and in finding the most effective cure for each case. The disease is caused by a mutation of the Rb-1 protein, which is a tumor suppressor. The disease is continuously being studied to find a way to prevent the disease.

Retinoblastoma is a disease that occurs in early childhood (usually before the age of five) and affects 1 in every 20,000. The majority of cases are discovered when a patient has a white pupil reflex or leukocoria. This is also called a catís eye reflex. The second most common manner is a crossed eye or strabismus. The eye(s) may turn towards the ear(s), which is called exotropia, or may turn towards the nose, which is called esotropia. Retinoblastoma is also discovered by presenting a red, painful eye, enlarged pupil, poor vision, and different colored irides (heterochromia). In rare cases, a patient may also experience failure to thrive, extra fingers and toes, and retardation.A patient can be bilateral or unilateral (affected in one or both eyes.) In the hereditary form, patients are more likely to have multiple tumors in both eyes. In the non-hereditary form, the most common, normally one eye is affected. The Rb gene is an important factor in this disease. Rb-1 is a tumor suppressor gene. Itís found in all cells of the body and acts as a brake on the cell division cycle by preventing certain regulatory proteins from triggering DNA replication. When Rb-1 is missing, a cell can replicate itself uncontrollably, resulting in a tumor. In the hereditary form of retinoblastoma, the Rb-1 gene is missing from the chromosome 13, which is responsible for controlling retinal cell division. The locus for retinoblastoma gene is in the region 13q14.1-14.2. Translated, itís on the long arm of chromosome 13. The treatment for retinoblastoma depends on the patientís age, whether theyíre bilateral or unilateral, and whether the cancer has spread. The most common treatment is called enucleation. This is where the eye is surgically removed. For unilateral patients, the eye is removed and a prosthesis is made to match identically. For bilateral patients, the ďworseĒ eye is removed and the other eye is treated with chemoreduction, cryotherapy or another treatment in attempts to save the childís vision. In cryotherapy, the smaller retinoblastoma tumors are frozen. This causes major swelling and isnít the best treatment for the disease. Chemoreduction is the treatment using chemotherapy. Itís given intravenously and causes the tumors to shrink within a few weeks if successful. One of the more effective treatments is external beam radiation. The tumors are extremely sensitive to radiation and usually shrink from this process. Unfortunately, this treatment can cause sunburns or patches of hair to fall out. Radioactive plaques and laser therapy are also available. When discovered early, the survival rate is 95%. 15% of unilateral and all

bilateral patients have a high risk of other cancers such as osteogenic sarcoma (tumors of

the skin, muscle, and connective tissue.) With yearly check-ups, the percent is lower.

It is known that retinoblastoma is caused by a mutation, or inactivation, of the Rb-1 protein. Splicing errors, point mutations and small deletions in the promoter region have also been observed as a cause. The pattern of inheritance is autosomal dominant. The chromosome is the esterase gene 13 at the q14 band. (To see diagram of chromosome and diagram of DNA sequence level, see attached sheet.) Studies have been done to map the disease to its particular loci. It was identified cytogenically. The Rb transcript was identified by chromosomal walking and Northern blotting with genomic DNA probes and subsequently cloned. DNA sequencing and molecular cloning was used to isolate the gene. The

restriction-fragment-length-polymorphism (RFLP) was identified within the

retinoblastoma gene and tested on their usefulness in predicting the risk of cancer in

patients with hereditary retinoblastoma. The gene was also studied by positional cloning.

The Rb-1 proteinís effect is seen during the G1 phase proceeding the restriction point. During the G1 phase, Rb is bound to the transcription factor E2F which prevents the S phase from initiating. Near the restriction point, Rb is phosphorylated by cdk4, 6-cyclin D kinases. The Rb then releases the E2F. The cell can then enter the S phase of the cycle.


If it is known that an immediate family member has retinoblastoma, then children are normally tested at birth. When there is no family history, then an examination is usually done when a parent notices leukocoria in their child. The child is examined by being given pupil-dilating drops which allows the doctor to view the retina with an indirect ophthalmoscope. This helps to determine the presence of tumors. Ultrasound examination uses sound waves to penetrate and outline structures in the eye and can determine a tumorís thickness or height. Treatments include different forms of chemotherapy and cryotherapy. Radiation causes tumors to shrink; therefore chemotherapy is often the best treatment. Another form of therapy is gene therapy. The textbook definition of gene therapy is ď a novel approach to treating diseases based on modifying the expression of a personís genes toward a therapeutic goal.Ē There are two types of gene therapy, somatic and germline, the latter being studied less do to ethical and technical reasons. Gene therapy entails removing the disease-causing components of the virus and inserting recombinant genes that will be beneficial to the patient. Studies are being done on gene therapy and how it will help battle retinoblastoma.

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