Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome - PubMed (original) (raw)

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Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome

Michel De Vos et al. Am J Hum Genet. 2004 May.

Abstract

We investigated a family with an autosomal recessive syndrome of cafe-au-lait patches and childhood malignancy, notably supratentorial primitive neuroectodermal tumor. There was no cancer predisposition in heterozygotes; nor was there bowel cancer in any individual. However, autozygosity mapping indicated linkage to a region of 7p22 surrounding the PMS2 mismatch-repair gene. Sequencing of genomic PCR products initially failed to identify a PMS2 mutation. Genome searches then revealed a previously unrecognized PMS2 pseudogene, corresponding to exons 9-15, within a 100-kb inverted duplication situated 600 kb centromeric from PMS2 itself. This information allowed a redesigned sequence analysis, identifying a homozygous mutation (R802X) in PMS2 exon 14. Furthermore, in the family with Turcot syndrome, in which the first inherited PMS2 mutation (R134X) was described, a further truncating mutation was identified on the other allele, in exon 13. Further whole-genome analysis shows that the complexity of PMS2 pseudogenes is greater than appreciated and may have hindered previous mutation studies. Several previously reported PMS2 polymorphisms are, in fact, pseudogene sequence variants. Although PMS2 mutations may be rare in colorectal cancer, they appear, for the most part, to behave as recessive traits. For technical reasons, their involvement in childhood cancer, particularly in primitive neuroectodermal tumor, may have been underestimated.

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Figures

Figure 1

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.

Figure 2

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.

Figure 3

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 ψ_13_-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).

Figure 4

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., ψ_1_). 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 ψ_2_–ψ_8_ 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.

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References

Electronic-Database Information

    1. MegaBLAST, http://www.ncbi.nlm.nih.gov/genome/seq
    1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim (for retinoblastoma, Li-Fraumeni syndrome, SMARCB1, NF1, and Turcot syndrome)
    1. PHYLIP, http://evolution.genetics.washington.edu/phylip.html
    1. RepeatMasker, http://woody.embl-heidelberg.de/repeatmask

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