Novel PMS2 Pseudogenes Can Conceal Recessive Mutations Causing a Distinctive Childhood Cancer Syndrome Michel De Vos, Bruce E. Hayward, Susan Picton,

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Novel PMS2 Pseudogenes Can Conceal Recessive Mutations Causing a Distinctive Childhood Cancer Syndrome Michel De Vos, Bruce E. Hayward, Susan Picton, Eamonn.

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Novel PMS2 Pseudogenes Can Conceal Recessive Mutations Causing a Distinctive Childhood Cancer Syndrome Michel De Vos, Bruce E. Hayward, Susan Picton, Eamonn Sheridan, David T. Bonthron The American Journal of Human Genetics Volume 74, Issue 5, Pages 954-964 (May 2004) DOI: 10.1086/420796 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree diagram. Linkage analysis was performed by use of DNA from the eight numbered individuals (IV-1–IV-4, V-2–V-4, V-6). Gray shading of the square representing patient V-6 indicates that he has CALS but no tumor. The American Journal of Human Genetics 2004 74, 954-964DOI: (10.1086/420796) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 a, Mutation analysis of PMS2 exon 14 (ABI377). Forward (F) and reverse (R) strand sequences are shown of uncloned PCR products generated by use of the published primer pair (upper panels) or the redesigned PMS2-specific primers (lower panels). The mutated codon is boxed, and the arrows indicate the mutated nucleotide. b, Exon 13 mutation in the patient with Turcot syndrome (Hamilton et al. 1995) (MegaBace). PCR products were cloned to show both deleted (top) and normal alleles. The lowercase nucleotides are the end of intron 12. The deleted dinucleotide (within a 2-nt repeat) is underlined, and the resulting predicted novel C-terminus is italicized. The American Journal of Human Genetics 2004 74, 954-964DOI: (10.1086/420796) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 Distribution of PMS2 pseudogenes and related sequences on chromosome 7. Symbols are as defined in the key. The members of the pseudogene-associated repeat family (PPJ repeats) can be classified by sequence similarity into two main subgroups (indicated by white and gray block arrows) and two outlying members (turquoise). The type 1 members (gray) appear to be the younger of the two main PPJ subgroups, having (with the exception of the ψ13-associated PPJ element) shorter distance branches on the phylogeny tree. Larger blocks of different colors indicate different higher-order repeat elements. Those shown in yellow and green correspond, respectively, to the type A and type C repeat elements identified elsewhere in studies of the Williams syndrome deletion region (Valero et al. 2000). (Other large repeat blocks in this region that are not associated with PPJ elements are not shown.) Numbers indicate the approximate positions (in Mb) of each PPJ element on the draft genome sequence (build 33). The American Journal of Human Genetics 2004 74, 954-964DOI: (10.1086/420796) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 4 Phylogenetic tree illustrating the relationships between the different members of the family with the 23-kb PPJ element. The tree was generated by using the DNADIST algorithm of the PHYLIP package to analyze a ClustalW-generated alignment of all 20 copies of a ∼1.5-kb segment of the PPJ element. (Details are available on request.) Branch lengths, therefore, give an indication of degree of divergence. The pseudogene-associated PPJ elements are referred to by the corresponding identity (e.g., ψ1). Those not associated with a pseudogene are given a number representing their sequence coordinate on chromosome 7 (National Center for Biotechnology Information [NCBI] release 33). The inset shows a tree generated from a subset of these PPJ elements by use of the same algorithm, to show more clearly the interrelationships of the closely similar ψ2–ψ8 PPJ elements. The structure of this tree implies that the local duplications leading to these PPJ clusters (and, hence, associated pseudogene clusters) occurred after the large-scale (∼100-kb) duplications around the Williams syndrome deletion region. The American Journal of Human Genetics 2004 74, 954-964DOI: (10.1086/420796) Copyright © 2004 The American Society of Human Genetics Terms and Conditions