Dataset Information

A parent-of-origin effect in two families with retinoblastoma is associated with a distinct splice mutation in the RB1 gene.

ABSTRACT: We have identified a splice-site mutation (IVS6+1G-->T) in the RB1 gene, in two unrelated families with incomplete-penetrance retinoblastoma. Analysis of RNA from white blood cells showed that this mutation causes skipping of exon 6. Although this deletion results in a frameshift, most carriers of the mutation did not develop retinoblastoma. Interestingly, the relative abundance of the resultant nonsense messenger RNA varies between members of the same family and is either similar to or considerably lower than the transcript level of the normal allele. Moreover, variation of relative transcript levels is associated with both the sex of the parent that transmitted the mutant allele and phenotypic expression: All eight carriers with similar abundance of nonsense and normal transcript have received the mutant allele from their mother, and only one of them has developed retinoblastoma; by contrast, all eight carriers with reduced abundance of the nonsense transcript have received the mutant allele from their father, and all but two them have retinoblastoma. After treatment with cycloheximide, the relative abundance of transcripts from paternally inherited mutant alleles was partly restored, thus indicating that posttranscriptional mechanisms, rather than transcriptional silencing, are responsible for low levels of mutant messenger RNA. Our data suggest that a specific RB1 mutation can be associated with differential penetrance, on the basis of the sex of the transmitting parent.

SUBMITTER: Klutz M

PROVIDER: S-EPMC384976 | biostudies-literature | 2002 Jul

REPOSITORIES: biostudies-literature

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A parent-of-origin effect in two families with retinoblastoma is associated with a distinct splice mutation in the RB1 gene.

Klutz Martina M Brockmann Dieter D Lohmann Dietmar R DR

American journal of human genetics 20020509 1

We have identified a splice-site mutation (IVS6+1G-->T) in the RB1 gene, in two unrelated families with incomplete-penetrance retinoblastoma. Analysis of RNA from white blood cells showed that this mutation causes skipping of exon 6. Although this deletion results in a frameshift, most carriers of the mutation did not develop retinoblastoma. Interestingly, the relative abundance of the resultant nonsense messenger RNA varies between members of the same family and is either similar to or consider ...[more]

PMID: 12016586

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Project description:Retinoblastoma (Rb), the most common pediatric intraocular neoplasm, results from inactivation of both alleles of the RB1 tumor suppressor gene. The second allele is most commonly lost, as demonstrated by loss of heterozygosity studies. RB1 germline carriers usually develop bilateral tumors, but some Rb families display low penetrance and variable expressivity. In order to decipher the underlying mechanisms, 23 unrelated low penetrance pedigrees segregating the common c.1981C>T/p.Arg661Trp mutation and other low penetrance mutations were studied. In families segregating the c.1981C>T mutation, we demonstrated, for the first time, a correlation between the gender of the transmitting carrier and penetrance, as evidenced by Fisher's exact test: the probability of being unaffected is 90.3% and 32.5% when the mutation is inherited from the mother and the father, respectively (p-value = 7.10(-7). Interestingly, a similar correlation was observed in families segregating other low penetrance alleles. Consequently, we investigated the putative involvement of an imprinted, modifier gene in low penetrance Rb. We first ruled out a MED4-driven mechanism by MED4 methylation and expression analyses. We then focused on the differentially methylated CpG85 island located in intron 2 of RB1 and showing parent-of-origin-specific DNA methylation. This differential methylation promotes expression of the maternal c.1981C>T allele. We propose that the maternally inherited c.1981C>T/p.Arg661Trp allele retains sufficient tumor suppressor activity to prevent retinoblastoma development. In contrast, when the mutation is paternally transmitted, the low residual activity would mimic a null mutation and subsequently lead to retinoblastoma. This implies that the c.1981C>T mutation is not deleterious per se but needs to be destabilized in order to reach pRb haploinsufficiency and initiate tumorigenesis. We suggest that this phenomenon might be a general mechanism to explain phenotypic differences in low penetrance Rb families.

Project description:PurposeRetinoblastomas are malignant eye tumors diagnosed in young children. Most retinoblastomas are genetically characterized by biallelic inactivation of the RB1 gene. However, 1.5% of tumors demonstrate high-level amplification of the proto-oncogene MYCN. Patients with MYCN-amplified RB1-proficient retinoblastoma receive a diagnosis at an earlier age and show a clinically and histologically more malignant phenotype. This study aimed to identify genome-wide molecular features that distinguish this subtype from other retinoblastomas.DesignCohort study.ParticipantsForty-seven retinoblastoma tumors, comprising 36 RB1 -/-, 4 RB1 +/-, and 7 RB1 +/+ tumors. In total, 5 retinoblastomas displayed high-level MYCN amplification, with 3 being RB1 +/+, 1 being RB1 +/-, and 1 being RB1 -/- .MethodsIntegrated analysis, based on gene expression, methylation, and methylation-expression correlations, was performed to identify distinct molecular components of MYCN-amplified RB1-proficient retinoblastomas compared with other retinoblastoma subtypes. The methylation and methylation-expression correlation analysis was initially conducted within a subset of samples (n = 15) for which methylation profiles were available. The significant findings were cross-validated in the entire cohort (n = 47) and in publicly available data.Main outcome measuresDifferentially expressed genes/pathways, differentially methylated genes, and methylation-driven differential gene expression.ResultsA large number of genes (n = 3155) were identified with distinct expression patterns in MYCN-amplified RB1-proficient retinoblastomas. The upregulated and downregulated genes were associated with translation and cell-cycle processes, respectively. Methylation analysis revealed distinct methylated patterns in MYCN-amplified RB1-proficient tumors, many of which showing significant impact on gene expression. Data integration identified a 40-gene expression signature with hypermethylated state resulting in a significant downregulation in MYCN-amplified RB1-proficient retinoblastomas. Cross-validation using the entire cohort and the public domain expression data verified the overall lower expression of these genes not only in retinoblastomas with a MYCN-amplified RB1-proficient background, but also in MYCN-amplified neuroblastomas. These include the metabolism-associated TSTD1 gene and the cyclin-dependent kinase inhibitor gene CDKN2C.ConclusionsMYCN-amplified RB1-proficient retinoblastomas display significantly distinct molecular features compared with other retinoblastomas, including a set of 40 hypermethylation-driven downregulated genes. This gene set can give insight into the biology of MYCN-amplified retinoblastomas and may help us to understand the more aggressive clinical behavior.

Dataset Information

A parent-of-origin effect in two families with retinoblastoma is associated with a distinct splice mutation in the RB1 gene.

Publications

A parent-of-origin effect in two families with retinoblastoma is associated with a distinct splice mutation in the RB1 gene.

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