Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

APC Splicing Mutations Leading to In-Frame Exon Skipping are Rare Events in FAP Pathogenesis and Define the Clinical Outcome

Version 1 : Received: 31 December 2020 / Approved: 4 January 2021 / Online: 4 January 2021 (11:59:26 CET)

How to cite: Disciglio, V.; Forte, G.; Fasano, C.; Sanese, P.; Lepore Signorile, M.; De Marco, K.; Grossi, V.; Cariola, F.; Simone, C. APC Splicing Mutations Leading to In-Frame Exon Skipping are Rare Events in FAP Pathogenesis and Define the Clinical Outcome. Preprints 2021, 2021010023 (doi: 10.20944/preprints202101.0023.v1). Disciglio, V.; Forte, G.; Fasano, C.; Sanese, P.; Lepore Signorile, M.; De Marco, K.; Grossi, V.; Cariola, F.; Simone, C. APC Splicing Mutations Leading to In-Frame Exon Skipping are Rare Events in FAP Pathogenesis and Define the Clinical Outcome. Preprints 2021, 2021010023 (doi: 10.20944/preprints202101.0023.v1).

Abstract

Familial adenomatous polyposis (FAP) is caused by germline mutations in the tumor suppressor gene APC. To date, nearly 2000 APC mutations have been described in FAP, most of which are predicted to result in truncated protein products. Mutations leading to aberrant APC splicing have rarely been reported. Here, we characterized a novel germline heterozygous splice donor site mutation in APC exon 12 (NM_000038.5: c.1621_1626+7del) leading to exon 12 skipping in an Italian family with the attenuated FAP (AFAP) phenotype. Moreover, we performed a literature me-ta-analysis of APC splicing mutations. We found that 123 unique APC splice site mutations, in-cluding the one described here, have been reported in FAP patients, 69 of which have been char-acterized at the mRNA level. Among these, only a small proportion (9/69) results in an in-frame protein, with 4 mutations causing skipping of exon 12 and/or 13 with loss of armadillo repeat 2 (ARM2) and 3 (ARM3), and 5 mutations leading to skipping of exon 5, 7, 8, and (partially) 9 with loss of regions not encompassing known functional domains. The APC splicing mutations considered in this study cluster with the AFAP phenotype and delineate a novel molecular mechanism of pathogenesis in FAP disease.

Subject Areas

Familial Adenomatous Polyposis; APC; Splicing; Exon Skipping; FAP Pathogenesis

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