title: PMS2 inactivation by a complex rearrangement involving an HERV retroelement and the inverted 100-kb duplicon on 7p22.1.
abstract: Biallelic PMS2 mutations are responsible for more than half of all cases of constitutional mismatch repair deficiency (CMMRD), a recessively inherited childhood cancer predisposition syndrome. The mismatch repair gene PMS2 is partly embedded within one copy of an inverted 100-kb low-copy repeat (LCR) on 7p22.1. In an individual with CMMRD syndrome, PMS2 was found to be homozygously inactivated by a complex chromosomal rearrangement, which separates the 5'-part from the 3'-part of the gene. The rearrangement involves sequences of the inverted 100-kb LCR and a human endogenous retrovirus element and may be associated with an inversion that is indistinguishable from the known inversion polymorphism affecting the ~0.7-Mb sequence intervening the LCR. Its formation is best explained by a replication-based mechanism (RBM) such as fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR). This finding supports the hypothesis that the inverted LCR can not only facilitate the formation of the non-allelic homologous recombination-mediated inversion polymorphism but it also promotes the occurrence of more complex rearrangements that can be associated with a large inversion, as well, but are mediated by a RBM. This further suggests that among the inversion polymorphism on 7p22.1, more complex rearrangements might be hidden. Furthermore, as the locus is embedded in a common fragile site (CFS) region, this rearrangement also supports the recently raised hypothesis that CFS sequence motifs may facilitate replication-based rearrangement mechanisms.
authors.affiliation: Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Vogt
authors.affiliation: Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Annekatrin
authors.initials: A
authors.lastname: Wernstedt
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Ripperger
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Pabst
authors.affiliation: Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.affiliation: Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kratz
authors.affiliation: Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Wimmer
mesh_terms: D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D043283:Chromosome Fragile Sites; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D020077:Endogenous Retroviruses / Q000235:genetics*; D015321:Gene Rearrangement; D006720:Homozygote; D006801:Humans; D008297:Male; D000070976:Mismatch Repair Endonuclease PMS2 / Q000235:genetics*; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis / Q000235:genetics*; D057345:Sequence Inversion
chemical_list: C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2