Constitutional nonsense germline mutations in the RB1 gene detected in patients with early onset unilateral retinoblastoma

Cowell, John K.; Cragg, Helen

doi:10.1016/0959-8049(96)00201-8

Cited by 17 publications

(7 citation statements)

References 24 publications

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“…By contrast, individuals who present without a family history and have only unilateral, unifocal tumors are generally considered not to carry germline mutations. While this distinction holds true in the vast majority of cases there is some overlap since approximately 2% of unilateral cases have a family history (Draper et al, 1992) and we have shown recently that unilateral cases who have a particularly early age of onset may also carry germline mutations (Cowell and Cragg, 1996). Within the hereditary group it is now clear that both alleles of the RB1 gene must be inactivated for tumorigenesis, supporting Knudson's original two-hit hypothesis (Knudson, 1971).…”

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confidence: 52%

A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype

Cowell

Bia

1998

Oncogene

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We have used single strand conformation polymorphism analysis to study the 27 exons of the RB1 gene in individuals from a family showing`mild' expression of the retinoblastoma phenotype. In this family a ected individuals developed unilateral tumors and, as a result of linkage analysis, una ected mutation carriers were also identi®ed within the pedigree. A single band shift using SSCP was identi®ed in exon 21 which resulted in a missense mutation converting a cys?arg at nucleotide position 28 in the exon. The mutation destroyed an NdeI restriction enzyme site. Analysis of all family members demonstrated that the missense mutation co-segregated with patients with tumors or who, as a result of linkage analysis had been predicted to carry the predisposing mutation. These observations point to another region of the RB1 gene where mutations only modify the function of the gene and raise important questions for genetic counseling in families with these distinctive phenotypes.

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confidence: 52%

A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype

Cowell

Bia

1998

Oncogene

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“…It has been inferred from Knudson's (1971) two-hit hypothesis that patients with an early presentation of unilateral tumors are likely to be carriers of a predispos-ing mutation (Cowell and Cragg 1996). Starting from this prediction, Cowell and Cragg (1996) investigated peripheral blood DNA of three patients with isolated unilateral retinoblastoma whose tumors were treated before the patients were 12 mo old, and they identified constitutional RB1-gene mutations in two of them. In our series, three patients treated before the age of 12 mo showed constitutional RB1-gene mutations, whereas, in seven patients, neither of the two mutations identified in the tumor was detected in peripheral blood.…”

Section: Imentioning

confidence: 99%

Constitutional RB1-Gene Mutations in Patients with Isolated Unilateral Retinoblastoma

Lohmann

Gerick

Brandt

et al. 1997

The American Journal of Human Genetics

142

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In most patients with isolated unilateral retinoblastoma, tumor development is initiated by somatic inactivation of both alleles of the RB1 gene. However, some of these patients can transmit retinoblastoma predisposition to their offspring. To determine the frequency and nature of constitutional RB1-gene mutations in patients with isolated unilateral retinoblastoma, we analyzed DNA from peripheral blood and from tumor tissue. The analysis of tumors from 54 (71%) of 76 informative patients showed loss of constitutional heterozygosity (LOH) at intragenic loci. Three of 13 uninformative patients had constitutional deletions. For 39 randomly selected tumors, SSCP, hetero-duplex analysis, sequencing, and Southern blot analysis were used to identify mutations. Mutations were detected in 21 (91%) of 23 tumors with LOH. In 6 (38%) of 16 tumors without LOH, one mutation was detected, and in 9 (56%) of the tumors without LOH, both mutations were found. Thus, a total of 45 mutations were identified in tumors of 36 patients. Thirty-nine of the mutations-including 34 small mutations, 2 large structural alterations, and hypermethylation in 3 tumors-were not detected in the corresponding peripheral blood DNA. In 6 (17%) of the 36 patients, a mutation was detected in constitutional DNA, and 1 of these mutations is known to be associated with reduced expressivity. The presence of a constitutional mutation was not associated with an early age at treatment. In 1 patient, somatic mosaicism was demonstrated by molecular analysis of DNA and RNA from peripheral blood. In 2 patients without a detectable mutation in peripheral blood, mosaicism was suggested because 1 of the patients showed multifocal tumors and the other later developed bilateral retinoblastoma. In conclusion, our results emphasize that the manifestation and transmissibility of retinoblastoma depend on the nature of the first mutation, its time in development, and the number and types of cells that are affected.

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“…These findings infer a role for pRB in controlling cell homing and invasion, the paracrine management of tissue morphogenesis and the promotion of lineage specific differentiation. Recent work has emphasized the importance of pRBmediated gene activation and gene repression in the prevention of tumor formation, suggesting that these activities may cooperate towards achieving effective tumor suppression (Sellers et al, 1998).The common type of RB1 alteration in patients with retinoblastoma are nonsense mutations predicted to result in the generation of severely truncated pRB forms with complete loss of all functional domains Gallie, 1994;Blanquet et al, 1995;Cowell and Cragg, 1996;Lohmann et al, 1996;Yilmaz et al, 1998;Lohmann, 1999;Alonso et al, 2001;Najera et al, 2001;Houdayer et al, 2004). However, in some instance the alterations have more subtle consequences, including the change, deletion or insertion of single amino acids or the alteration of intronic sequences, which perturbs or prevents correct splicing of the transcript.…”

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A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity

et al. 2005

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Hereditary predisposition to retinoblastoma is caused by germ line mutations in the RB1 gene. Genetic counseling of affected individuals and accurate risk prediction for their families requires identification of the disease causing mutation. Furthermore, the nature of a mutation can determine genetic penetrance, disease presentation and prognosis. We describe, and functionally characterize here, a novel mutant allele of RB1 present in the germ line of a patient with sporadic bilateral retinoblastoma. The mutation generates an operational splice acceptor site resulting in a predicted protein product with loss of 81 amino acids from its carboxy terminus. We demonstrate that the aberrantly spliced transcript is present in substantial amounts in peripheral blood of the patient and present evidence that the predicted protein product displays partial loss of activity reflecting in degree and presentation that of the partially penetrant RB1 missense mutant R661W. This infers that disease with reduced expressivity and incomplete penetrance may arise in individuals that carry the mutation and predicts such presentation for similar mutations with found in sporadic cases in the past. © 2004 Wiley-Liss, Inc.KEY WORDS: retinoblastoma; reduced expressivity; penetrance; splicing; RB1; pRB INTRODUCTIONRetinoblastoma, a childhood tumor of the eye, is caused by inactivation in the developing human retina of both alleles of the RB1 tumor suppressor gene (MIM# 180200) (reviewed in DiCiommo et al., 2000). In hereditary retinoblastoma (accounting for roughly 50% of cases) one RB1 allele is mutated in the germ line as either a novel or an inherited mutation. In this instance disease usually presents at an early age, with multiple tumor foci in both eyes, a high incidence of disease recurrence, increased lifetime risk for secondary malignancies and transmission to kindred with a penetrance of greater 95%. In its nonhereditary form mutational inactivation of both RB1 alleles DOI: 10.1002/humu.9305 2 Sánchez-Sánchez et al.arises from somatic events in a single retinal cell. Here disease presentation is far milder disease featuring late onset, single tumor foci in one eye only and absence of recurrence and secondary tumor development. In rare instance hereditary retinoblastoma can present in a form reminiscent to the non-hereditary disease (reduced expressivity), and often in this instance shows reduced penetrance in kindred (low penetrance).The product of the human RB1 gene (p110RB/pRB) is a nuclear phospho-protein composed of 928 amino acids. Through interacting with cellular proteins pRB influences cell proliferation, but also other types of cell behavior (reviewed in Kaelin, 1999;Zheng and Lee, 2001). Most noted is the function of pRB to control gene transcription via E2F (reviewed in Harbour and Dean, 2000;Stevens and La Thangue, 2003). Through association with specific members of this transcription factor family pRB represses genes required for cell cycle progression and proliferation, and by attracting additional chromatin modifyin...

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Constitutional nonsense germline mutations in the RB1 gene detected in patients with early onset unilateral retinoblastoma

Cited by 17 publications

References 24 publications

A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype

A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype

Constitutional RB1-Gene Mutations in Patients with Isolated Unilateral Retinoblastoma

A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity

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