Activation of a Cryptic Splice Site of PTEN and Loss of Heterozygosity in Benign Skin Lesions in Cowden Disease Stephen J. Meltzer, Manfred Wolter Journal.

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Activation of a Cryptic Splice Site of PTEN and Loss of Heterozygosity in Benign Skin Lesions in Cowden Disease Stephen J. Meltzer, Manfred Wolter Journal of Investigative Dermatology Volume 117, Issue 6, Pages 1650-1653 (December 2001) DOI: 10.1046/j.0022-202x.2001.01954.x Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Mutation analysis of PTEN. (a) Pedigree of a family with classical Cowden disease. Phenotypically affected family members are denoted by filled symbols. Numbers indicate the age of diagnosis with a malignant tumor. Underlined, index patient; BT, brain tumor; DCIS, ductal carcinoma in situ of the breast; STS, soft-tissue sarcoma; *, blood available for PTEN mutation analysis. (b) A heterozygous PTEN germline mutation of the 5′-splice acceptor site of exon 2 (IVS2 + 1G > A) was identified in the index patient (II.1), whereas a phenotypically unaffected grandson (IV.1) carried only the wildtype sequence (arrowheads). Journal of Investigative Dermatology 2001 117, 1650-1653DOI: (10.1046/j.0022-202x.2001.01954.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 RT-PCR amplification and subcloning of PTEN transcripts from a patient with Cowden disease. (a) PTEN wildtype transcript sequence was found in eight of 10 clones (upper panel), but two clones carried a 5 bp deletion at the 3′ site of PTEN exon 2 (lower panel), which is predicted to result in a truncated protein. (b) Size differences between wildtype (lanes 1–6, 10, and 11) and cryptic spliced PTEN transcripts (lanes 8# and 9#) were not detected. One (lane 7*) out of 60 clones carried an insert of larger size. (c) Sequence analysis of this clone showed a complex rearrangement with partial retention of PTEN intron 1 and skipping of exon 2. The retained intronic sequence contained a 76 bp sequence of the 5′ site of intron 1 followed by 81 bp of a further downstream “exon-like” sequence of intron 1. Journal of Investigative Dermatology 2001 117, 1650-1653DOI: (10.1046/j.0022-202x.2001.01954.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 LOH analysis in benign mucocutaneous lesions of a patient with CD. (a) Fluorescent microsatellite analysis of the intragenic PTEN microsatellite marker D10S249. Compared with PCR products generated from peripheral blood mononuclear cells (upper panel) DNA extracted from a paraffin-embedded acanthoma demonstrated LOH (lower panel, arrowhead). (b) Sequencing analysis showed hemizygosity for the wildtype allele at PTEN IVS2 + 1, indicating loss of the mutant allele. Journal of Investigative Dermatology 2001 117, 1650-1653DOI: (10.1046/j.0022-202x.2001.01954.x) Copyright © 2001 The Society for Investigative Dermatology, Inc Terms and Conditions