Transcript dosage effect in familial adenomatous polyposis: Model offered by two kindreds with exon 9 APC gene mutations

Abstract

Analysis of genotype-phenotype correlations in familial adenomatous polyposis (FAP) patients demonstrated that the phenotypic heterogeneity of FAP is partly related to the mutation site. We investigated the molecular basis for the difference in severity of colorectal disease observed comparing FAP patients from two kindreds with neighbouring germline mutations in exon 9 of the APC gene. Patients from one kindred presented with a attenuated form of FAP, characterized by a low number of colorectal adenomas (up to 22). In FAP patients from this kindred, the APC gene mutation was localized at codon 367, in the portion of exon 9 that is alternately spliced. This is expected to result in the splicing-out of the mutation site in a fraction of mRNA molecules and in the residual production of wild-type transcripts from the mutant APC allele. Patients from the other kindred manifested a FAP phenotype characterized by hundreds of colorectal adenomas (320 to > 500). In these patients, the APC gene mutation abolished the donor site of exon 9a, used in both alternately spliced isoforms of the exon. The analysis of the relative levels of mutant and wild-type transcripts in unaffected colonic mucosa demonstrated that the mutant allele was not expressed. The model offered by our FAP patients with neighbouring exon 9 APC mutations supports the view that in addition to the mutation site, the type of mutation and transcript dosage effects contribute to the heterogeneity of disease phenotypes.

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

“…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.…”

Explaining differences in the severity of familial adenomatous polyposis and the search for modifier genes

“…It is possible that the mild disease of AAPC results because many patients can produce a near fully functional APC protein by splicing out the exon containing their germline mutation from the APC mRNA. One study has found evidence that the severity of disease in an AAPC family with exon 9 mutations was associated with the levels of alternative mRNA splice variants of this exon48; in other words, the relative levels of the truncated (and possibly unstable) protein and the splice variant protein determined disease severity. Candidate genes for AAPC modifiers must act in trans ; APC itself is the best candidate for effects on mRNA splicing but disease severity would not then segregate independently of disease.…”

A novel indel in exon 9 of APC upregulates a ‘skip exon 9’ isoform and causes very severe familial adenomatous polyposis

“…5,6 Consequently, any mutation 5 0 to exon 9a would most likely result in an aFAP phenotype. It was thus very surprising to note that the colonic manifestation in the proband was very severe, compared with that of the mother and the uncle.…”

“…Mutation in residues 5 0 to exon 9a often results in an attenuated form of FAP (aFAP), with later age of onset (usually in the fourth and the fifth decade of life) and fewer (o100) polyps. 5,6 This is due to the splicingout of the mutation site in a fraction of mRNA molecules and in the residual production of shorter, in-frame transcripts from the mutant APC allele. Hence, exon 9a modulates the effect of any mutation in the 5 0 end of exon 9, resulting in the aFAP phenotype.…”