The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis

Abstract

Juvenile polyposis (JPS) is an autosomal dominant syndrome that predisposes individuals to develop gastrointestinal polyps and cancer. Germline point mutations in SMAD4 and BMPR1A have been identified as causing JPS in approximately 40-60% of patients, but few studies have looked at the rate of large deletions. In this study, we determined the overall prevalence of genetic changes of SMAD4 and BMPR1A by sequencing and by screening for larger deletions. DNA was extracted from 102 JPS probands, and each exon and intron-exon boundary of SMAD4 and BMPR1A were sequenced. Coding and non-coding exons of SMAD4 and BMPR1A were screened for deletions with multiplex ligation-dependent probe amplification (MLPA). By sequencing, 20 probands had point mutations of SMAD4 and 22 of BMPR1A. By MLPA, one proband had deletion of most of SMAD4, one of both BMPR1A and PTEN, one of the 5' end of BMPR1A, and another of the 5' end of SMAD4. The overall prevalence of SMAD4 and BMPR1A point mutations and deletions in JPS was 45% in the largest series of patients to date. Large deletions are less frequent in JPS patients, but represent other heritable causes of JPS, which should be screened for in pre-symptomatic genetic testing.

The growing complexity of the intestinal polyposis syndromes

“…Mutations of either SMAD4 or BMPR1A are found in about 50-60% of JPS patients [Aretz et al, 2006;van Hattem et al, 2008;Calva-Cerqueira et al, 2009]. Other types of polyps, adenomatous, hyperplastic, and of mixed histology have been reported in families with BMPR1A mutations .…”

Repository of SMAD4 Mutations: Reference for Genotype/ Phenotype Correlation

“…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].…”

“…The majority of missense mutations caused SMAD4 protein charge alterations in exons 10 (Arg361Ser/Gly/Cys/His, Glu330Lys/Gly, Gly352Arg, Cys324Arg and Cys363Arg), 11 (Gly386Asp and Glu390Lys) and 13 (Asp493Ala and Trp509Arg) [7,8,14,15,20,22,[25][26][27][28][29][30]unpublished ARUP data]. The remaining missense mutations from exons 10 and 13 altered the size rather than the charge of the amino acid from the SMAD4 MH2 domain (Tyr353Ser, Leu364Trp, Gly491Val, Gly510Val, Trp524Leu and Leu533Val) [3,7,14,18,20,22,29].…”

“…The majority of missense mutations caused SMAD4 protein charge alterations in exons 10 (Arg361Ser/Gly/Cys/His, Glu330Lys/Gly, Gly352Arg, Cys324Arg and Cys363Arg), 11 (Gly386Asp and Glu390Lys) and 13 (Asp493Ala and Trp509Arg) [7,8,14,15,20,22,[25][26][27][28][29][30]unpublished ARUP data]. The remaining missense mutations from exons 10 and 13 altered the size rather than the charge of the amino acid from the SMAD4 MH2 domain (Tyr353Ser, Leu364Trp, Gly491Val, Gly510Val, Trp524Leu and Leu533Val) [3,7,14,18,20,22,29]. 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].…”

“…The remaining missense mutations from exons 10 and 13 altered the size rather than the charge of the amino acid from the SMAD4 MH2 domain (Tyr353Ser, Leu364Trp, Gly491Val, Gly510Val, Trp524Leu and Leu533Val) [3,7,14,18,20,22,29]. 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].…”