Molecular Etiology of Low-Penetrance Retinoblastoma in Two Pedigrees

Dryja, Thaddeus P.; Rapaport, Joyce M.; McGee, Terri L.; Nork, T. Michael; Schwartz, Terry L.

doi:10.1097/00006982-199401000-00030

Cited by 70 publications

(85 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus it appears as if the binding of TAF II 250 by Rb requires a di erent region(s) of the large pocket than do other conventional pocket-binding proteins. Given that it has already been shown that Rb can interact with multiple transcription factors simultaneously (Weintraub et al, (Dryja et al, 1993;Hogg et al, 1993). There appear to be at least two domains in TAF II 250 important for binding the large pocket of Rb (Figure 8).…”

Section: Discussionmentioning

confidence: 96%

Rb interacts with TAFII250/TFIID through multiple domains

Shao

Siegert

Ruppert³

et al. 1997

Oncogene

View full text Add to dashboard Cite

The retinoblastoma tumor suppressor gene product (Rb) binds directly to the largest TFIID subunit, TATAbinding protein associated factor TAF II 250, ®rst identi®ed as the cell cycle regulatory protein CCG1. Here we map the domains in Rb and TAF II 250 important for their interaction in vitro and in vivo. Both the amino terminus and the large pocket of Rb are able to associate independently with TAF II 250. The binding domain(s) within the large pocket are distinct from the viral oncoprotein and E2F binding region since certain pocket mutations, which abolish E1A binding, do not abolish TAF II 250 binding. Consistent with the large pocket of Rb binding to TAF II 250, the large pocket domains of both p107 and p130 are able to bind to TAF II 250 in vivo. We also demonstrate that at least two regions of TAF II 250 are able to bind to the large pocket of Rb independently whereas the amino terminus of Rb binds to a distinct domain in TAF II 250. We further demonstrate that Rb can bind to TFIID in vitro, presumably in part through an interaction with TAF II 250. Our results suggest a complex interaction between Rb and TAF II 250 and imply that TAF II 250, TFIID, and potentially other basal transcription factors are targets for regulation by Rb and Rb-related proteins.

show abstract

Section: Discussionmentioning

confidence: 96%

Rb interacts with TAFII250/TFIID through multiple domains

Shao

Siegert

Ruppert³

et al. 1997

Oncogene

View full text Add to dashboard Cite

show abstract

“…If mistakenly classified as oncogenic patients may be misadvised as to transmission of the disease and kindred at risk might not be identified. These issues emphasize the importance of demonstrating that functional consequences result from hitherto unidentified mutations.Alterations of subtle type have been seen in rare families with low disease penetrance and mild disease presentation and characterization of transcript and the predicted mutant protein products revealed partial, incomplete or selective loss of activity in such cases (Dryja et al, 1993;Kratzke et al, 1994;Bremner et al, 1997;Otterson et al, 1997;Sanchez et al, 2000;Scheffer et al, 2000;Klutz et al, 2002), reviewed in (Harbour, 2001. This led to the hypothesis that residual pRB functioning may reduce tumor incidence and/ or dampen progression of disease.…”

mentioning

confidence: 99%

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

et al. 2005

View full text Add to dashboard Cite

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...

show abstract

“…These phenomena have been reported in several genetic disorders, i.e., congenital heart disease, (4) type II diabetes, (5) cystic fibrosis, (6) Hirschsprung disease, (7) erythropoietic protoporphyria (EPP), (8) retinitis pigmentosa 11, (9) and retinoblastoma. (10,11) A large family segregating retinoblastoma was described by Dryja et al, in which a germline deletion in the RB gene encompassing exon 4 was detected both in the affected children and one of their unaffected parents. (10) The lack of satisfactory mechanistic explanations for the phenomena led Vogel and Motulsky to refer to IP-VE as ''labels of our ignorance'' (Human Genetics: Principles and Approaches, 1997, third edition).…”

Section: Introductionmentioning

confidence: 99%

“…(10,11) A large family segregating retinoblastoma was described by Dryja et al, in which a germline deletion in the RB gene encompassing exon 4 was detected both in the affected children and one of their unaffected parents. (10) The lack of satisfactory mechanistic explanations for the phenomena led Vogel and Motulsky to refer to IP-VE as ''labels of our ignorance'' (Human Genetics: Principles and Approaches, 1997, third edition). However, in the recent years there has been considerable advances in the understanding of the basis of IP-VE in specific cases.…”

Section: Introductionmentioning

confidence: 99%

Incomplete penetrance and variable expressivity: is there a microRNA connection?

et al. 2009

View full text Add to dashboard Cite

Incomplete penetrance and variable expressivity are non‐Mendelian phenomena resulting in the lack of correlation between genotype and phenotype. Not withstanding the diversity in mechanisms, differential expression of homologous alleles within cells manifests as variations in penetrance and expressivity of mutations between individuals of the same genotype. These phenomena are seen most often in dominantly inherited diseases, implying that they are sensitive to concentration of the gene product. In this framework and the advances in understanding the role of microRNA (miRNA) in fine‐tuning gene expression at translational level, we propose miRNA‐mediated regulation as a mechanism for incomplete penetrance and variable expressivity. The presence of miRNA binding sites at 3′ UTR, co‐expression of target gene–miRNA pairs for genes showing incomplete penetrance and variable expressivity derived from available data lend support to our hypothesis. Single nucleotide polymorphisms in the miRNA target site facilitate the implied differential targeting of the transcripts from homologous alleles.

show abstract

Molecular Etiology of Low-Penetrance Retinoblastoma in Two Pedigrees

Cited by 70 publications

References 29 publications

Rb interacts with TAFII250/TFIID through multiple domains

Rb interacts with TAFII250/TFIID through multiple domains

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

Incomplete penetrance and variable expressivity: is there a microRNA connection?

Contact Info

Product

Resources

About