De novo mutations in familial adenomatous polyposis (FAP)

TY - JOUR

T1 - De novo mutations in familial adenomatous polyposis (FAP)

AU - Ripa, Rasmus Sejersten

AU - Bisgaard, Marie Luise

AU - Bülow, Steffen

AU - Nielsen, Finn Cilius

PY - 2002/10

Y1 - 2002/10

N2 - Familial Adenomatous Polyposis (FAP) results from a germline mutation in the APC gene. A new mutation rate of 4-9 x 10(-6) mutations/gametes/generation has been reported. In other familial cancer syndromes a bias for paternal origin of new mutations has been described. This bias is probably due to a larger number of cell divisions during spermatogenesis compared to oogenesis; giving a larger susceptibility for mutagenesis. We report here a molecular genetic analysis of 26 FAP patients with putative de novo APC mutations. In 15 families the novel origin of the mutations was confirmed by haplotyping and sequencing. Analysis of 10 of these mutations, in which the parental origin could be established, gave a 6 : 4 distribution in favour of maternal origin. This is in agreement with a 1 : 1 distribution and does not indicate an expected paternal bias. Moreover, no parental age effect was identified. We propose that APC germline mutations are not premeiotic events but more likely arise during the meiosis. This would give an equal susceptibility for mutagenesis during spermatogenesis and oogenesis, respectively. The model is in concordance with the previously established difference between APC somatic mutations, as being a mitotic event and APC germline mutations, as being a meiotic event. The confirmation of 15 de novo mutations by a molecular genetic approach is in fine agreement with previous results based on clinical records.

AB - Familial Adenomatous Polyposis (FAP) results from a germline mutation in the APC gene. A new mutation rate of 4-9 x 10(-6) mutations/gametes/generation has been reported. In other familial cancer syndromes a bias for paternal origin of new mutations has been described. This bias is probably due to a larger number of cell divisions during spermatogenesis compared to oogenesis; giving a larger susceptibility for mutagenesis. We report here a molecular genetic analysis of 26 FAP patients with putative de novo APC mutations. In 15 families the novel origin of the mutations was confirmed by haplotyping and sequencing. Analysis of 10 of these mutations, in which the parental origin could be established, gave a 6 : 4 distribution in favour of maternal origin. This is in agreement with a 1 : 1 distribution and does not indicate an expected paternal bias. Moreover, no parental age effect was identified. We propose that APC germline mutations are not premeiotic events but more likely arise during the meiosis. This would give an equal susceptibility for mutagenesis during spermatogenesis and oogenesis, respectively. The model is in concordance with the previously established difference between APC somatic mutations, as being a mitotic event and APC germline mutations, as being a meiotic event. The confirmation of 15 de novo mutations by a molecular genetic approach is in fine agreement with previous results based on clinical records.

KW - Adenomatous Polyposis Coli

KW - Adult

KW - Denmark

KW - Female

KW - Genes, APC

KW - Humans

KW - Male

KW - Mutation

KW - Pedigree

KW - Sequence Deletion

U2 - 10.1038/sj.ejhg.5200853

DO - 10.1038/sj.ejhg.5200853

M3 - Journal article

C2 - 12357334

SN - 1018-4813

VL - 10

SP - 631

EP - 637

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 10

ER -