Allele separation facilitates interpretation of potential splicing alterations and genomic rearrangements

Hidewaki Nakagawa, Hai Yan, Janet Lockman, Heather Hampel, Kenneth W. Kinzler, Bert Vogelstein, Albert De la Chapelle

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Mutations that alter normal splice patterns and genomic rearrangements are common causes of hereditary diseases including hereditary nonpolyposis colorectal cancer. However, abnormal transcripts can be difficult to detect and interpret because splicing patterns are often heterogeneous even in normal cells. Standard techniques including sequencing and Southern hybridization fail to detect some genomic rearrangements. We show here that separation of alleles in somatic cell hybrids, through "conversion" technology, considerably facilitates the interpretation of abnormal splicing patterns and the detection of genomic rearrangements. We detected novel mutations in MLH1 in each of four hereditary nonpolyposis colorectal cancer patients. The genomic mutations were CAG>CAA predicting Q346Q; GAG>AAG predicting E102K; a>g at nucleotide 1559-2 at intron 13, and a tandem duplication involving exons 7-12. By separating the two alleles, we showed that one allele produced only abnormal transcript or no transcript whereas the other allele produced only normal transcript. These results allowed pathogenicity to be unambiguously assigned to the mutations and increased the sensitivity of genomic testing.

Original languageEnglish (US)
Pages (from-to)4579-4582
Number of pages4
JournalCancer Research
Issue number16
StatePublished - Aug 15 2002

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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