Mutational screening of the RB1 gene in Italian patients with retinoblastoma reveals 11 novel mutations

Abstract

Retinoblastoma (RB, OMIM#180200) is the most common intraocular tumour in infancy and early childhood. Constituent mutations in the RB1 gene predispose individuals to RB development. We performed a mutational screening of the RB1 gene in Italian patients affected by RB referred to the Medical Genetics of the University of Siena. In 35 unrelated patients, we identified germline RB1 mutations in 6 out of 9 familial cases (66%) and in 7 out of 26 with no family history of RB (27%). Using the single-strand conformational polymorphism (SSCP) technique, 11 novel mutations were detected, including 3 nonsense, 5 frameshift and 4 splicesite mutations. Only two of these mutations (1 splice site and 1 missense) were previously reported. The mutation spectrum reflects the published literature, encompassing predominately nonsense or frameshift and splicing mutations. RB1 germline mutation was detected in 37% of our cases. Gross rearrangements outside the investigated region, altered DNA methylation, or mutations in non-coding regions, may be the cause of disease in the remainder of the patients. Some cases, e.g. a case of incomplete penetrance, or variable expressivity ranging from retinoma to multiple tumours, are discussed in detail. In addition, a case of pre-conception genetic counselling resolved by rescue of banked cordonal blood of the affected deceased child is described.

Retinoblastoma epidemiology: Does the evidence matter?

“…In a recent paper appeared on the Journal of Human Genetics, Sampieri and Coll., 82 having found a mutation rate of 37% in a series of Italian patients with 'hereditary retinoblastoma', conclude that: 'The mutation rate reported in the study is quite similar to that found by other groups using the same methodological approach' and that, given the disappointing results of this investigation, '. .…”

pRb2/p130: a new candidate for retinoblastoma tumor formation

“…The majority of germline mutations that have been identified in patients with hereditary retinoblastoma are nonsense or frameshift mutations, mostly located in the exons 1-25 of the RB1 gene (Sampieri et al, 2005). These kinds of mutations will lead to abortive transcripts that will be degraded, leaving only the transcript of the normal allele.…”

p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma

“…2 Penetrance and expressivity of hereditary RB may depend on the type of inherited mutation, and can vary even within families and among patients with identical mutations. [3][4][5] This indicates a role of modifiers that may affect genome stability to favor the occurrence of somatic mutations, and/or the apoptotic pathway to induce loss or maintenance of the mutated retinoblasts.The p53 pathway, the master control system of these processes, is controlled by a feedback autoregulatory loop in which p53 transcriptionally activates MDM2, that in turn functions as a negative regulator by promoting the proteolytic degradation of p53. Interestingly, this circuit can also target pRB to degradation and in physiological condition controls the cell cycle and apoptosis of the retinal cone precursors, from which the RB cell lineage originates.…”

“…2 Penetrance and expressivity of hereditary RB may depend on the type of inherited mutation, and can vary even within families and among patients with identical mutations. [3][4][5] This indicates a role of modifiers that may affect genome stability to favor the occurrence of somatic mutations, and/or the apoptotic pathway to induce loss or maintenance of the mutated retinoblasts.…”