Retinoblastoma Is Caused by Two Mutations

In 1971 Knudson hypothesized that two mutational events are sufficient for development of retinoblastoma (two-mutation model).[2] Later, molecular analysis showed that the two mutations alter both alleles of a single gene, the retinoblastoma gene (RB1).[6] This gene was cloned in

1986[3] and the finding of inactivating mutations confirmed Knudson's two-mutation hypothesis:[7'8]

• Familial retinoblastoma is caused by germ-line mutations in the RB1 gene. Family members that have inherited a mutant RB1 allele from a parent are at a high risk because only one mutation that alters the remaining normal allele is sufficient for complete functional loss of the retinoblastoma gene. Second mutations can occur in several retinal precursor cells and each of these cells may be the beginning of an independent tumor focus.

• Most patients with sporadic bilateral retinoblastoma are heterozygous for a mutant RB1 allele. This mutation has either occurred de novo in germ-line cells of one of the parents (most often in the germ line of the father) or is inherited from a parent who is a carrier of the mutation but has not developed retinoblastoma (incomplete penetrance). Tumors arise from retinal precursor cells that have acquired mutational loss of the second RB1 allele.

• Mutational inactivation of the RB1 gene is also a prerequisite for tumor development in patients with sporadic unilateral retinoblastoma. In most of these patients, both RB1 gene mutations occur in somatic cells and none of the two somatic mutations is detectable in DNA from peripheral blood.[9]

In recent years, molecular analysis in patients with retinoblastoma has shown that Knudson's original model needs to be extended:

• In some patients with sporadic bilateral or unilateral retinoblastoma the predisposing RB1 gene mutation is present in a mosaic state.[9,10] Mutational mosa-icism occurs when the first mutation has occurred de novo during embryonic development of the child. It has to be assumed that in some children with muta-tional mosaicism the mutation is present in only a sector of retinal precursor cells. Tumor development can only occur in cells that are part of the mutant sector. This may account for the observation that patients with mosaicism for a given mutation develop fewer tumors than patients who are heterozygous for the same mutation.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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