Retinoblastoma (RB) is a rare intraocular tumour that occurs predominantly in children below the age of five. There are heritable and sporadic forms, both resulting from inactivation of the tumour-suppressor gene RB1. The sporadic form occurs when both copies of the RB1 gene are inactivated within the same retinoblast cell. As this is a rare event, the disease is typically unilateral and unifocal. In heritable retinoblastoma, an inherited or newly acquired germline mutation inactivates one allele in every cell. Mutation or loss of the second allele is then very likely in at least one retinoblast, and multiple tumours are common. Thus, familial RB usually shows dominant inheritance with high penetrance and bilateral disease.A small subset of families with heritable RB exhibit reduced penetrance. Obligate carriers either remain disease-free or they only develop a unifocal tumour more typical of sporadic RB. Most mutations identified in these families are predicted to alter, but not abolish, protein function. Otterson et al.1xTemperature-sensitive RB mutations linked to incomplete penetrance of familial retinoblastoma in 12 families. Otterson, G.A. et al. Am. J. Hum. Genet. 1999; 65: 1040–1046Abstract | Full Text | Full Text PDF | PubMed | Scopus (27)See all References1 studied the effects of three RB1 mutations associated with low-penetrance RB. All the mutations are situated within the pocket-binding domain of the protein, which is crucial for tumour-suppressor activity, and have previously been shown to have defective pocket-binding. However, in assays carried out in yeast grown at 30°C, they found that the pocket-binding activity was significantly greater than that observed at 37°C. This was true for each of the three mutations, and binding was further enhanced at 24°C. Temperature-sensitivity is not a new phenomenon, but this study documents significant fluctuations in pocket-binding activity simply by altering in vitro culture temperature. Minor variations in ambient conditions, temperature or otherwise, might similarly influence activity of the mutant protein in vivo. These subtle mutations will aid further understanding of RB protein function but, most excitingly, one might speculate that if the pocket-binding activity could be stably enhanced, then perhaps retinoblastoma could be prevented in patients carrying these particular mutations.