De novo mutations in familial adenomatous polyposis (FAP)
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De novo mutations in familial adenomatous polyposis (FAP). / Ripa, Rasmus Sejersten; Bisgaard, Marie Luise; Bülow, Steffen; Nielsen, Finn Cilius.
I: European Journal of Human Genetics, Bind 10, Nr. 10, 10.2002, s. 631-7.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
VL - 10
SP - 631
EP - 637
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 10
ER -
ID: 47744817