Abstract
A number of phenotypes in hereditary disorders or common diseases are associated with specific genotypes. However, little is known about the molecular basis of phenotypic variation among individuals carrying the same mutation or polymorphism. Here, a highly quantitative approach was taken to examine a relative amount of mRNA from two polymorphic alleles with a coefficient of variation of less than 10% using an RNA difference plot (RDP). RDP analysis revealed that most genes examined were expressed in equal amount from the two alleles in normal lymphocytes. In contrast, the relative amounts of hMSH2 or RB1 mRNAs carrying premature termination codons were significantly reduced compared with those of wild-type mRNAs in lymphocytes from carriers of hereditary, nonpolyposis, colorectal cancer and hereditary retinoblastoma. The balance of allelic expression of the RB1 was also significantly impaired in a pedigree of retinoblastoma carrying a missense mutation in codon 661. The relative expression of the mutant to the wild-type RB1 alleles among the carriers varied from 0.40 to 2.39. The analysis of the expression diversity of a disease-associated allele by RDP could provide a novel approach to elucidating the mechanisms underlying phenotypic variation among individuals carrying an identical mutation or polymorphism at a single locus.
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Acknowledgements
We thank Drs. Raymond L. White, Roger H. Reeves, and Noboru Sueoka for their valuable comments and suggestions. This work was partially supported by a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and a Grant from the Program for Promotion of Fundamental Studies in Health Sciences of the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan.
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Murakami, Y., Isogai, K., Tomita, H. et al. Detection of allelic imbalance in the gene expression of hMSH2 or RB1 in lymphocytes from pedigrees of hereditary, nonpolyposis, colorectal cancer and retinoblastoma by an RNA difference plot. J Hum Genet 49, 635–641 (2004). https://doi.org/10.1007/s10038-004-0201-0
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DOI: https://doi.org/10.1007/s10038-004-0201-0
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