A novel APC promoter 1B deletion shows a founder effect in Italian patients with classical familial adenomatous polyposis phenotype

M. Marabelli, V. Gismondi, M. T. Ricci, A. Vetro, R. Abou Khouzam, V. Rea, M. Vitellaro, O. Zuffardi, L. Varesco, G. N. Ranzani

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Familial adenomatous polyposis is a Mendelian syndrome in which germline loss-of-function mutations of APC are associated with multiple adenomatous polyps of the large bowel, a multiplicity of extracolonic features, and a high lifetime risk of colorectal cancer. Different APC germline mutations have been identified, including sequence changes, genomic rearrangements, and expression defects. Recently, very rare families have been associated with constitutive large deletions encompassing the APC-5' regulatory region, while leaving the remaining gene sequence intact; the regulatory region contains a proximal and a distal promoter, called 1A and 1B, respectively. We identified a novel deletion encompassing promoter 1B in a large Italian family that manifested polyposis in three of the six branches descending from a founding couple married in 1797. By combining different molecular approaches on both DNA and RNA, we precisely mapped this deletion (6858 bp in length) that proved to be associated with APC allele silencing. The finding of the same deletion in two additional polyposis families pointed to a founder mutation in Italy. Deletion carriers from the three families all showed a "classical" polyposis phenotype. To explore the molecular mechanisms underlying promoter deletions, we performed an in silico analysis of the breakpoints of 1A and 1B rearrangements so far reported in the literature; moreover, to decipher genotype-phenotype correlations, we critically reviewed current knowledge on deletions versus point mutations in the APC-5' regulatory region.
Original languageEnglish
Pages (from-to)846-854
Number of pages9
JournalGenes Chromosomes and Cancer
Volume56
Issue number12
DOIs
Publication statusPublished - Dec 1 2017

Fingerprint

Founder Effect
Adenomatous Polyposis Coli
Nucleic Acid Regulatory Sequences
Phenotype
Adenomatous Polyps
Mutation
Germ-Line Mutation
Genetic Association Studies
Point Mutation
Computer Simulation
Italy
Colorectal Neoplasms
Alleles
RNA
DNA
Genes

Keywords

  • Adenomatous Polyposis Coli/genetics/pathology
  • Adenomatous Polyposis Coli Protein/genetics
  • Adolescent
  • Adult
  • Female
  • Founder Effect
  • Gene Deletion
  • Germ-Line Mutation
  • Humans
  • Italy
  • Male
  • Middle Aged
  • Pedigree
  • Phenotype
  • Promoter Regions, Genetic

Cite this

A novel APC promoter 1B deletion shows a founder effect in Italian patients with classical familial adenomatous polyposis phenotype. / Marabelli, M.; Gismondi, V.; Ricci, M. T.; Vetro, A.; Khouzam, R. Abou; Rea, V.; Vitellaro, M.; Zuffardi, O.; Varesco, L.; Ranzani, G. N.

In: Genes Chromosomes and Cancer, Vol. 56, No. 12, 01.12.2017, p. 846-854.

Research output: Contribution to journalArticle

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T1 - A novel APC promoter 1B deletion shows a founder effect in Italian patients with classical familial adenomatous polyposis phenotype

AU - Marabelli, M.

AU - Gismondi, V.

AU - Ricci, M. T.

AU - Vetro, A.

AU - Khouzam, R. Abou

AU - Rea, V.

AU - Vitellaro, M.

AU - Zuffardi, O.

AU - Varesco, L.

AU - Ranzani, G. N.

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N2 - Familial adenomatous polyposis is a Mendelian syndrome in which germline loss-of-function mutations of APC are associated with multiple adenomatous polyps of the large bowel, a multiplicity of extracolonic features, and a high lifetime risk of colorectal cancer. Different APC germline mutations have been identified, including sequence changes, genomic rearrangements, and expression defects. Recently, very rare families have been associated with constitutive large deletions encompassing the APC-5' regulatory region, while leaving the remaining gene sequence intact; the regulatory region contains a proximal and a distal promoter, called 1A and 1B, respectively. We identified a novel deletion encompassing promoter 1B in a large Italian family that manifested polyposis in three of the six branches descending from a founding couple married in 1797. By combining different molecular approaches on both DNA and RNA, we precisely mapped this deletion (6858 bp in length) that proved to be associated with APC allele silencing. The finding of the same deletion in two additional polyposis families pointed to a founder mutation in Italy. Deletion carriers from the three families all showed a "classical" polyposis phenotype. To explore the molecular mechanisms underlying promoter deletions, we performed an in silico analysis of the breakpoints of 1A and 1B rearrangements so far reported in the literature; moreover, to decipher genotype-phenotype correlations, we critically reviewed current knowledge on deletions versus point mutations in the APC-5' regulatory region.

AB - Familial adenomatous polyposis is a Mendelian syndrome in which germline loss-of-function mutations of APC are associated with multiple adenomatous polyps of the large bowel, a multiplicity of extracolonic features, and a high lifetime risk of colorectal cancer. Different APC germline mutations have been identified, including sequence changes, genomic rearrangements, and expression defects. Recently, very rare families have been associated with constitutive large deletions encompassing the APC-5' regulatory region, while leaving the remaining gene sequence intact; the regulatory region contains a proximal and a distal promoter, called 1A and 1B, respectively. We identified a novel deletion encompassing promoter 1B in a large Italian family that manifested polyposis in three of the six branches descending from a founding couple married in 1797. By combining different molecular approaches on both DNA and RNA, we precisely mapped this deletion (6858 bp in length) that proved to be associated with APC allele silencing. The finding of the same deletion in two additional polyposis families pointed to a founder mutation in Italy. Deletion carriers from the three families all showed a "classical" polyposis phenotype. To explore the molecular mechanisms underlying promoter deletions, we performed an in silico analysis of the breakpoints of 1A and 1B rearrangements so far reported in the literature; moreover, to decipher genotype-phenotype correlations, we critically reviewed current knowledge on deletions versus point mutations in the APC-5' regulatory region.

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KW - Adenomatous Polyposis Coli Protein/genetics

KW - Adolescent

KW - Adult

KW - Female

KW - Founder Effect

KW - Gene Deletion

KW - Germ-Line Mutation

KW - Humans

KW - Italy

KW - Male

KW - Middle Aged

KW - Pedigree

KW - Phenotype

KW - Promoter Regions, Genetic

U2 - 10.1002/gcc.22488 [doi]

DO - 10.1002/gcc.22488 [doi]

M3 - Article

VL - 56

SP - 846

EP - 854

JO - Genes Chromosomes and Cancer

JF - Genes Chromosomes and Cancer

SN - 1045-2257

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ER -