First genetic analysis in Tunisian familial adenomatous polyposis probands

Bougatef, Karim; Marrakchi, Raja; Moussa, Amel; Blondeau-Lahely, Yannick; Najjar, Tawfik; Coulet, Florence; Colas, Chrystelle; Ayed, Farhat Ben; Elgaaied, Amel Ben Ammar; Soubrier, Florent

doi:10.3892/or.19.5.1213

Cited by 3 publications

(3 citation statements)

References 21 publications

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“…The method of the DNA amplifying is achieved by the PCR into 32 separate segments using primers for the entire coding region of the APC gene and exons 7 and 13 of MUTYH (which harbor the two common MUTYH mutations G382D and Y165C) [60, 61]. …”

Section: Pathogenesis: Molecular Genetics Diet Relationship Syndmentioning

confidence: 99%

Precancerous Lesions in Colorectal Cancer

Sandouk¹,

Jerf²,

Al-Halabi

2013

Gastroenterology Research and Practice

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Colorectal cancer (CRC) is the third most common cause of cancer death in the world. The incidence rate (ASR) and age distribution of this disease differ between most of African-Middle-Eastern (AMAGE) and North America and Europe for many reasons. However, in all areas, “CRC” is considered as one of the most preventable cancers, because it might develop from variant processes like polyps and IBD in addition to the genetic pathogenesis which became very well known in this disease. We tried in this paper to review all the possible reasons of the differences in incidence and age between the west and AMAGE. Also we reviewed all the mutations that lead to the hereditary and familiar clustering of this disease with the correlations with the surrounding food and environment of different areas. Then, we focused on the precancerous pathology of this disease with special focusing on early detection depending on new endoscopy technology and most important genetic studies. We lastly reviewed the evidence of some of the surveillance and put suggestions about future surveillance programs and how important those programs are on the psychological aspect of the patients and their families.

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Section: Pathogenesis: Molecular Genetics Diet Relationship Syndmentioning

confidence: 99%

Precancerous Lesions in Colorectal Cancer

Sandouk¹,

Jerf²,

Al-Halabi

2013

Gastroenterology Research and Practice

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“…All APC and MUTYH exons were amplified by polymerase chain reaction (PCR) in a total volume of 30 µl of reaction mixture containing 100 ng of genomic DNA of each sample, 1X PCR buffer, 2.5 mM Mgcl 2 , 10 mM dNTP, 3.3 µM of each primers as previously described (14) (Table S1, Supporting Information) and 1U Ampli Taq Gold® DNA polymerase (Applied Biosystems, Foster City, CA). Amplification was performed on a GeneAmp PCR system 9700 (Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

Frequent mutation in North African patients with MUTYH-associated polyposis

Lefèvre

Colas²,

Coulet³

et al. 2010

Clinical Genetics

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MUTYH-associated polyposis (MAP) has been characterized as an autosomal recessive disease predisposing to a variable number of colorectal adenomas with a high risk of cancer. Numerous studies have indicated that two missense mutations (Y179C and G396D) account for about 80% of MUTYH allelic variants in Europeans. Ethnic and geographic differences in the mutation spectrum have been observed. The aim of this study was to report mutations in patients from North Africa, determine the incidence of the c.1227_1228dup mutation in our cohort of MUTYH patients and to evaluate the existence of a founder effect. Within a group of 36 families with MAP, 11 were shown to have a homozygous c.1227_1228dup mutation. These families came from Algeria (n = 5), Tunisia (n = 4), Morocco (n = 1) and Portugal (n = 1). Probands belonging to families of North African origin showed a significantly higher frequency of c.1227_1228dup (78.6% vs 4.5%, p < 0.0001). Haplotype analyses were performed using 10 microsatellite markers surrounding the MUTYH gene spanning a region of 4.4 cM. We identified a common haplotype of at least 1.3 cM in all families suggesting a founder effect for this mutation.

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“…The remaining molecularly characterized splicing mutations leading to an in-frame protein (5/9) result in skipping of exon 5, 7, 8, or (partially) 9 with loss of APC regions not encompassing known functional sites/domains [45,54,67] (Table S3). In order to provide further insight into the relationship between APC exon 12 or exon 13 splicing mutations leading to an in-frame protein, the clinical phenotype, and the potential underlying molecular mechanisms in FAP disease, we retrieved clinical and molecular data of FAP patients bearing truncating mutations that lead to partial or total removal of ARM2 and/or ARM3 and disrupt all downstream APC protein domains [50,53,71,[89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105] (Table S4). Then, we sought to compare the phenotypic consequences of splicing mutations leading to in-frame amino acid deletions within the ARM2 or ARM3 motifs of the APC protein N-terminal armadillo repeat domain with those of truncating mutations located in the ARM2 (aa 505-547) or ARM3 (aa 548-591) domains leading to partial or total removal of ARM2 and/or ARM3 and disrupting all APC downstream regions (aa 505-2843), including the β-catenin-regulating domains (Figure 4).…”

Section: Meta-analysismentioning

confidence: 99%

APC Splicing Mutations Leading to In-Frame Exon 12 or Exon 13 Skipping Are Rare Events in FAP Pathogenesis and Define the Clinical Outcome

Disciglio

Forte

Fasano

et al. 2021

Genes

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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 meta-analysis of APC splicing mutations. We found that 119 unique APC splicing mutations, including the one described here, have been reported in FAP patients, 69 of which have been characterized at the mRNA level. Among these, only a small proportion (9/69) results in an in-frame protein, with four mutations causing skipping of exon 12 or 13 with loss of armadillo repeat 2 (ARM2) and 3 (ARM3), and five mutations leading to skipping of exon 5, 7, 8, or (partially) 9 with loss of regions not encompassing known functional domains. The APC splicing mutations causing skipping of exon 12 or 13 considered in this study cluster with the AFAP phenotype and reveal a potential molecular mechanism of pathogenesis in FAP disease.

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First genetic analysis in Tunisian familial adenomatous polyposis probands

Cited by 3 publications

References 21 publications

Precancerous Lesions in Colorectal Cancer

Precancerous Lesions in Colorectal Cancer

Frequent mutation in North African patients with MUTYH-associated polyposis

APC Splicing Mutations Leading to In-Frame Exon 12 or Exon 13 Skipping Are Rare Events in FAP Pathogenesis and Define the Clinical Outcome

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