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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Wimmer K, Kratz CP : Constitutional mismatch repair-deficiency syndrome. Haematologica 2010; 95: 699–701.
Vasen H, Ghorbanoghli Z, Bourdeaut F et al: Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium ‘Care for CMMR-D’(C4CMMR-D). J Med Genet 2014; 51: 283–293.
Wimmer K, Kratz CP, Vasen HF et al: Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD). J Med Genet 2014; 51: 355–365.
De Vos M, Hayward BE, Picton S, Sheridan E, Bonthron DT : Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am J Hum Genet 2004; 74: 954–964.
Hayward BE, De Vos M, Valleley EM et al: Extensive gene conversion at the PMS2 DNA mismatch repair locus. Hum Mutat 2007; 28: 424–430.
Ganster C, Wernstedt A, Kehrer-Sawatzki H et al: Functional PMS2 hybrid alleles containing a pseudogene-specific missense variant trace back to a single ancient intrachromosomal recombination event. Hum Mutat 2010; 31: 552–560.
van der Klift HM, Tops CM, Bik EC et al: Quantification of sequence exchange events between PMS2 and PMS2CL provides a basis for improved mutation scanning of Lynch syndrome patients. Hum Mutat 2010; 31: 578–587.
Auclair J, Leroux D, Desseigne F et al: Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum Mutat 2007; 28: 1084–1090.
Wernstedt A, Valtorta E, Armelao F et al: Improved multiplex ligation-dependent probe amplification analysis identifies a deleterious PMS2 allele generated by recombination with crossover between PMS2 and PMS2CL. Genes Chromosomes Cancer 2012; 51: 819–831.
Feuk L, MacDonald JR, Tang T et al: Discovery of human inversion polymorphisms by comparative analysis of human and chimpanzee DNA sequence assemblies. PLoS Genet 2005; 1: e56.
Szamalek JM, Cooper DN, Schempp W et al: Polymorphic micro-inversions contribute to the genomic variability of humans and chimpanzees. Hum Genet 2006; 119: 103–112.
Beck CR, Carvalho CM, Banser L et al: Complex genomic rearrangements at the PLP1 locus include triplication and quadruplication. PLoS Genet 2015; 11: e1005050.
Lee JA, Carvalho CM, Lupski JR : A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 2007; 131: 1235–1247.
Hastings P, Ira G, Lupski JR : A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet 2009; 5: e1000327.
Liu P, Carvalho CM, Hastings P, Lupski JR : Mechanisms for recurrent and complex human genomic rearrangements. Curr Opin Genet Dev 2012; 22: 211–220.
Hastings P, Lupski JR, Rosenberg SM, Ira G : Mechanisms of change in gene copy number. Nat Rev Genet 2009; 10: 551–564.
Arlt MF, Mulle JG, Schaibley VM et al: Replication stress induces genome-wide copy number changes in human cells that resemble polymorphic and pathogenic variants. Am J Hum Genet 2009; 84: 339–350.
Zhang F, Khajavi M, Connolly AM, Towne CF, Batish SD, Lupski JR : The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nat Genet 2009; 41: 849–853.
Gu W, Zhang F, Lupski JR : Mechanisms for human genomic rearrangements. Pathogenetics 2008; 1: 4.
Carvalho CM, Ramocki MB, Pehlivan D et al: Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome. Nat Genet 2011; 43: 1074–1081.
Zhang F, Seeman P, Liu P et al: Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability. Am J Hum Genet 2010; 86: 892–903.
Hsiao MC, Piotrowski A, Callens T et al: Decoding NF1 intragenic copy-number changes. Am J Hum Genet 2015; 97: 238–249.
Etzler J, Peyrl A, Zatkova A et al: RNA-based mutation analysis identifies an unusual MSH6 splicing defect and circumvents PMS2 pseudogene interference. Hum Mutat 2008; 29: 299–305.
Andreutti-Zaugg C, Scott RJ, Iggo R : Inhibition of nonsense-mediated messenger RNA decay in clinical samples facilitates detection of human MSH2 mutations with an in vivo fusion protein assay and conventional techniques. Cancer Res 1997; 57: 3288–3293.
Hendriks YM, Jagmohan-Changur S, van der Klift HM et al: Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology 2006; 130: 312–322.
Wimmer K, Wernstedt A : PMS2 gene mutational analysis: direct cDNA sequencing to circumvent pseudogene interference. Pseudogenes: Springer 2014; 1167: 289–302.
Carvalho CM, Pehlivan D, Ramocki MB et al: Replicative mechanisms for CNV formation are error prone. Nat Genet 2013; 45: 1319–1326.
Carvalho CM, Zhang F, Liu P et al: Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Hum Mol Genet 2009; 18: 2188–2203.
Bosco N, Pelliccia F, Rocchi A : Characterization of FRA7B, a human common fragile site mapped at the 7p chromosome terminal region. Cancer Genet Cytogenet 2010; 202: 47–52.
Lukusa T, Fryns J-P : Human chromosome fragility. Biochim Biophys Acta 2008; 1779: 3–16.
Mrasek K, Schoder C, Teichmann A-C et al: Global screening and extended nomenclature for 230 aphidicolin-inducible fragile sites, including 61 yet unreported ones. Int J Oncol 2010; 36: 929–940.
Arlt M, Casper A, Glover T : Common fragile sites. Cytogenet Genome Res 2003; 100: 92–100.
Arlt MF, Durkin SG, Ragland RL, Glover TW : Common fragile sites as targets for chromosome rearrangements. DNA Repair 2006; 5: 1126–1135.
Zlotorynski E, Rahat A, Skaug J et al: Molecular basis for expression of common and rare fragile sites. Mol Cell Biol 2003; 23: 7143–7151.
Dillon LW, Burrow AA, Wang Y-H : DNA instability at chromosomal fragile sites in cancer. Curr Genomics 2010; 11: 326.
Aguilera A, García-Muse T : R loops: from transcription byproducts to threats to genome stability. Mol Cell 2012; 46: 115–124.
Helmrich A, Ballarino M, Tora L : Collisions between replication and transcription complexes cause common fragile site instability at the longest human genes. Mol Cell 2011; 44: 966–977.
Le Tallec B, Koundrioukoff S, Wilhelm T, Letessier A, Brison O, Debatisse M : Updating the mechanisms of common fragile site instability: how to reconcile the different views? Cell Mol Life Sci 2014; 71: 4489–4494.
Casper AM, Nghiem P, Arlt MF, Glover TW : ATR regulates fragile site stability. Cell 2002; 111: 779–789.
Rothkamm K, Krüger I, Thompson LH, Löbrich M : Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol 2003; 23: 5706–5715.
Mitsui J, Takahashi Y, Goto J et al: Mechanisms of genomic instabilities underlying two common fragile-site-associated loci, PARK2 and DMD, in germ cell and cancer cell lines. Am J Hum Genet 2010; 87: 75–89.
van der Klift HM, Tops CM, Hes FJ, Devilee P, Wijnen JT : Insertion of an SVA element, a nonautonomous retrotransposon, in PMS2 intron 7 as a novel cause of Lynch syndrome. Hum Mutat 2012; 33: 1051–1055.
Borràs E, Pineda M, Cadiñanos J et al: Refining the role of PMS2 in Lynch syndrome: germline mutational analysis improved by comprehensive assessment of variants. J Med Genet 2013; 50: 552–563.
Vaughn CP, Baker CL, Samowitz WS, Swensen JJ : The frequency of previously undetectable deletions involving 3′ exons of the PMS2 gene. Genes Chromosomes Cancer 2013; 52: 107–112.
Acknowledgements
We thank the technical staff of the Institute of Human Genetics in Innsbruck for excellent technical support and the Helmholtz Institute, Munich, Germany for performing the CytoScan HD analysis.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on European Journal of Human Genetics website
Supplementary information
Rights and permissions
About this article
Cite this article
Vogt, J., Wernstedt, A., Ripperger, T. et al. PMS2 inactivation by a complex rearrangement involving an HERV retroelement and the inverted 100-kb duplicon on 7p22.1. Eur J Hum Genet 24, 1598–1604 (2016). https://doi.org/10.1038/ejhg.2016.75
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/ejhg.2016.75
This article is cited by
-
Detecting inversions in routine molecular diagnosis in MMR genes
Familial Cancer (2022)
-
Seltene Tumordispositionssyndrome mit Manifestation im Kindesalter
Medizinische Genetik (2017)
