A splicing mutation in RB1 in low penetrance retinoblastoma

Schubert, Elizabeth L.; Strong, Louise C.; Hansen, Marc F.

doi:10.1007/s004390050551

Cited by 42 publications

(35 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, there is a rule behind genotype-phenotype associations that becomes clear when mutations with identical effects on the transcript are compared. For example, distinct splice mutations result in an in-frame loss of exon 21 (Patients T8 and T14, mutations reported [Nichols et al, 2005, Schubert et al, 1997Taylor et al, 2007] and unpublished mutations). All substitutions at g.160835 (IVS2111) are associated with bilateral retinoblastoma and complete penetrance (DER 5 2, eight patients in three families).…”

Section: Discussionmentioning

confidence: 94%

Patterns of missplicing caused byRB1gene mutations in patients with retinoblastoma and association with phenotypic expression

et al. 2008

View full text Add to dashboard Cite

We have analyzed RNA from retinoblastoma patients and unaffected carriers with various RB1 gene mutations to determine the patterns of missplicing and associations with phenotypic expression. Most sequence alterations in or in the neighborhood of conserved splice signals that we tested resulted in simple exon skipping (15 mutations) or intron inclusion (new acceptor AG-sites, four mutations) as expected. Two mutations resulted in skipping of a neighboring exon (exon 11), a complex pattern indicating competition for correct lariat formation. We observed no activation of a cryptic splice site but found that a recurrent missense mutation in exon 7 creates a new splice site (two families). RT-PCR analysis enabled us to confirm the presence and to characterize the transcriptional consequences of gross insertions and deletions in the RB1 gene in six patients, including two patients with mutational mosaicism. We also used RT-PCR analysis to search for unknown mutations in 15 patients and identified three oncogenic point mutations deep in introns. Two of these mutations are recurrent thus indicating that, despite the vast extent of the introns of the RB1 gene, few bases are effective targets for oncogenic mutations. When analyzing associations between phenotypic expression (16 families) and mutational consequences we observed no link to the presence or absence of a premature termination codon in the mutant transcript. However, the location of a mutation relative to the splice sequence has a strong and consistent influence on phenotypic expression.

show abstract

Section: Discussionmentioning

confidence: 94%

Patterns of missplicing caused byRB1gene mutations in patients with retinoblastoma and association with phenotypic expression

et al. 2008

View full text Add to dashboard Cite

show abstract

“…This basic model has been challenged by investigations of genotype-phenotype correlations that reported specific LP or ''weak'' alleles in a small number of families [Ahmad et al, 1999;Bremner et al, 1997;Cowell et al, 1996;Dryja et al, 1993;Klutz et al, 2002;Kratzke et al, 1994;Lohmann et al, 1994;Onadim et al, 1992;Otterson et al, 1997Otterson et al, , 1999Sakai et al, 1991;Scheffer et al, 2000;Schubert et al, 1997;Seminara and Dryja, 1994].…”

Section: Discussionmentioning

confidence: 96%

Genotype–phenotype correlations in hereditary familial retinoblastoma

et al. 2007

View full text Add to dashboard Cite

We studied 50 unrelated pedigrees with a family history of retinoblastoma (Rb) (165 carriers of a RB1 mutation) to delineate the spectrum of RB1 germline mutations in familial Rb and to identify genotype-phenotype correlations as well as putative modifiers. Patients were followed at Institut Curie and they were examined by an ophthalmologist, a pediatrician, and a geneticist. All cases of familial Rb were determined via genetic counseling. Clinical features included disease status, laterality, age at diagnosis, mutation type, follow-up, and disease-eye ratio (DER). To eliminate mosaic cases, first-generation carriers displaying low-penetrance (LP) Rb were excluded from the analysis. Complete penetrance was the rule for nonsense and frameshift mutations (25 families) and high penetrance was observed for large rearrangements (eight families). Promoter (two families) and missense (two families) mutations displayed heterogeneous phenotypes and LP. Variable penetrance was observed for splice abnormalities (13 families) and was explained by in/out of frame mutations or respect of functional domains. Surprisingly, two families with the LP g.45867G>T/IVS6+1G>T mutation presented data that conflicted with the data reported in previous publications, as unaffected carriers had paternally inherited mutant alleles. Moreover, RNA analyses suggested that the lack of penetrance in unaffected carriers could be explained by an increase in expression levels of the wild-type allele. This observation prompted us to define a new class "3" of LP alleles. We believe this is the first large-scale study of familial Rb with a high level of homogeneity in the clinical and genetic analysis of patients and their relatives, thereby allowing for reliable intrafamilial genotype-phenotype correlations. Our analysis suggests in some cases the influence of modifier factors probably involved in mRNA level regulation and/or pRB pathway regulation.

show abstract

“…The reason why missense mutations of the MEN1 gene located in close proximity are associated with typical MEN1 on the one hand, and cosegregate with FIHP on the other, is unclear. Of relevance in this regard is the finding that, in familial adenomatous polyposis (23) and familial retinoblastoma (24), kindreds with low penetrance and expressivity show gene mutations resulting in the splicing-out of the mutation site in a fraction of mRNA and in the residual production of wild-type transcripts from the mutant allele. Viewed in this light, the late onset and the reduced penetrance of disease observed in the present family may be explained by the site of the mutation.…”

Section: Discussionmentioning

confidence: 99%

A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism

Honda

Tsukada²,

Tanaka³

et al. 2000

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: To determine whether familial isolated hyperparathyroidism (FIHP) is a variant of multiple endocrine neoplasia type 1 (MEN1) we analyzed the MEN1 gene in such a kindred. Design and methods:The study included the 70-year-old proband and nine relatives. Blood was drawn for biochemical evaluation and germline mutation analysis by direct sequencing of the MEN1 gene amplified by PCR. A hyperplastic parathyroid gland obtained from a family member served for a loss of heterozygosity (LOH) study. Results: Three members from two generations in this kindred were found to have primary hyperparathyroidism, while none had clinical or biochemical evidence of MEN1, MEN2 or hyperparathyroidismjaw tumor syndrome. Analysis of germline DNA in the proband showed a missense mutation (GGC → GAC) at codon 305 in exon 7 of the MEN1 gene that predicts an amino acid change from glycine to aspartic acid (G305D). This mutation segregated with primary hyperparathyroidism in the kindred, and, in addition, there were two asymptomatic mutant-gene carriers at relatively advanced ages. In contrast, the mutation was not detected in genomic DNA from five unaffected individuals and from 50 healthy subjects. The LOH study showed a loss of the wild-type allele, which confirmed that a functional defect of the MEN1 gene product, menin, is etiological for FIHP. Conclusions: FIHP is a genetically heterogeneous disease with a subset linked to MEN1, most likely representing a variant of MEN1. The late onset and the reduced penetrance of disease found in this kindred may be related to the site and the type of mutation, although the precise mechanism involved is unknown at present.

show abstract

A splicing mutation in RB1 in low penetrance retinoblastoma

Cited by 42 publications

References 36 publications

Patterns of missplicing caused byRB1gene mutations in patients with retinoblastoma and association with phenotypic expression

Patterns of missplicing caused byRB1gene mutations in patients with retinoblastoma and association with phenotypic expression

Genotype–phenotype correlations in hereditary familial retinoblastoma

A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism

Contact Info

Product

Resources

About