Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers

Abstract

Juvenile polyposis syndrome (JPS) is an autosomal dominant predisposition to multiple juvenile polyps in the gastrointestinal tract. Germline mutations in the MADH4 or BMPR1A genes have been found to be causative of the disease in a subset of JPS patients. So far, no genotype-phenotype correlation has been reported. We examined 29 patients with the clinical diagnosis of JPS for germline mutations in the MADH4 or BMPR1A genes and identified MADH4 mutations in seven (24%) and BMPR1A mutations in five patients (17%). A remarkable prevalence of massive gastric polyposis was observed in patients with MADH4 mutations when compared with patients with BMPR1A mutations or without identified mutations. This is the first genotype-phenotype correlation observed in JPS.

Bone Morphogenetic Protein Signaling Suppresses Tumorigenesis at Gastric Epithelial Transition Zones in Mice

“…This leads to the phosphorylation of the type I receptor that subsequently phosphorylates the BMP-specific Smads (Smad1, Smad5, and Smad8), allowing these receptor-associated Smads to form a complex with Smad4 and move into the nucleus where the Smad complex binds a DNA binding protein and acts as a transcriptional enhancer (5). BMPs regulate apoptosis of intestinal epithelial cells (6) and mutations in the BMP receptor 1a (BMPR1A) have been found in f20% of families with juvenile polyposis syndrome whereas another 20% of cases of juvenile polyposis syndrome are caused by mutations in SMAD4, the common mediator of BMP and TGF-h signaling (7)(8)(9). Mice with a conditional inactivation of the Bmpr1a (10) and mice that overexpress a BMP antagonist in the intestine (11) have an intestinal phenotype that resembles Juvenile polyposis with the development of multiple hamartomatous polyps in the intestine.…”

Repository of SMAD4 Mutations: Reference for Genotype/ Phenotype Correlation

“…Despite this, several genotype/phenotype correlations have been made among individuals with JPS caused by SMAD4 versus BMPR1A mutations. Patients with JPS caused by a SMAD4 mutation are more likely to have upper-GI polyps compared to those with BMPR1A or no known mutations and individuals with either a SMAD4 or BMPR1A mutation are more likely than those without mutations identified in these genes to have a more severe phenotype (more than ten lower GI polyps and a family history of GI cancer) [8,15,16].…”

“…Mutations predicted to lead to a frameshift and eventually cause the formation of a premature stop codon were found in exon 10 (4 deletions and 1 insertion), exon 11 (3 deletions), exon 12 (4 deletions and 1 insertion) and exon 13 (3 deletions, 2 insertions and 2 duplications) [3,4,7,8,14,[16][17][18][19][20][21][22]26,28,30,unpublished ARUP results]. Six nonsense mutations that also caused a premature stop codon to form were identified in exons 11 (c.1162C>T, p.Glu388X; c.1193G>A, p.Trp398X; c.1236C>G, p.Tyr412X), 12 (c.1333C>T, p.Arg445X; c.1342C>T, p.Gln448X) and 13 (c.1527G>A, p.Trp509X) [3,7,8,14,16,21,22,[26][27][28]31]. Two mutations predicted to alter splicing in this region were found in intron 10 (c.1139G>A and c.1139+1G>A) [14,20,22].…”

“…No missense mutations were located in exons 1-9. Mutations predicted to lead to a frameshift leading to a premature stop codon were found in exon 3 (an insertion/deletion), exon 4 (1 duplication and 1 insertion), exon 5 (1 deletion), exon 6 (2 deletions), exon 7 (2 insertions), exon 8 (2 deletions) and exon 9 (1 duplication) [3,4,7,8,14,16,17,20,22,26,34,35]. Four nonsense mutations that lead to a premature stop codon were also identified in exon 4 (c.403C>T, p.Arg135X) and exon 6 (c.437T>A, p.Leu146X; c.533C>G, p.Ser178X; c.538C>T, p.Gln180X) [14,18,20,29,34].…”

Polipose juvenil: relato de 2 casos

“…Em 2004, um total de 141 pacientes foram testados para mutação no gene SMAD4 em 6 estudos (Friedl et al (12) , WoodfordRichens et al (13) , Howe et al (14,15) , Roth et al (16) , Kim et al (17) ) 32 (22,7%) pacientes apresentaram mutação positiva. Esta mutação provoca perda da inibição do crescimento celular e inibição da apoptose (alteração do fator de crescimento transformador beta -TGF â) com crescimento do componente mesenquimal o que resulta em displasia epitelial e progressão neoplásica (8) .…”