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This Article Full Text Free Full Text (PDF) Free Supplemental Data All Versions of this Article: fj.09-129098v1 23/6/2001    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Toyoda, Y. Articles by Ishikawa, T. Search for Related Content PubMed PubMed Citation Articles by Toyoda, Y. Articles by Ishikawa, T.

Earwax, osmidrosis, and breast cancer: why does one SNP (538G>A) in the human ABC transporter ABCC11 gene determine earwax type?

Yu Toyoda^*, Aki Sakurai^*,, Yasumasa Mitani^,, Masahiro Nakashima, Koh-ichiro Yoshiura^||, Hiroshi Nakagawa^*, Yasuo Sakai^¶, Ikuko Ota^,#, Alexander Lezhava, Yoshihide Hayashizaki, Norio Niikawa^||,** and Toshihisa Ishikawa^*,,1

^* Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan;

Omics Science Center (OSC), RIKEN Yokohama Institute, Yokohama, Japan;

K.K. DNAFORM, Yokohama, Japan;

Tissue and Histopathology Section, Atomic Bomb Disease Institute, and

^|| Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan;

^¶ Department of Plastic and Reconstructive Surgery, Fujita Health University, Toyoake, Japan;

^# Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan; and

^** Research Institute of Personalized Health Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan

¹Correspondence: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B-60 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan. E-mail: tishikaw{at}bio.titech.ac.jp

One single-nucleotide polymorphism (SNP), 538G>A (Gly180Arg), in the ABCC11 gene determines the type of earwax. The G/G and G/A genotypes correspond to the wet type of earwax, whereas A/A corresponds to the dry type. Wide ethnic differences exist in the frequencies of those alleles, reflecting global migratory waves of the ancestors of humankind. We herein provide the evidence that this genetic polymorphism has an effect on the N-linked glycosylation of ABCC11, intracellular sorting, and proteasomal degradation of the variant protein. Immunohistochemical studies with cerumen gland-containing tissue specimens revealed that the ABCC11 WT protein was localized in intracellular granules and large vacuoles, as well as at the luminal membrane of secretory cells in the cerumen gland, whereas granular or vacuolar localization was not detected for the SNP (Arg180) variant. This SNP variant lacking N-linked glycosylation is recognized as a misfolded protein in the endoplasmic reticulum and readily undergoes ubiquitination and proteasomal degradation, which determines the dry type of earwax as a mendelian trait with a recessive phenotype. For rapid genetic diagnosis of axillary osmidrosis and potential risk of breast cancer, we developed specific primers for the SmartAmp method that enabled us to clinically genotype the ABCC11 gene within 30 min.—Toyoda, Y., Sakurai, A., Mitani, Y., Nakashima, M., Yoshiura, K., Nakagawa, H., Sakai, Y., Ota, I., Lezhava, A., Hayashizaki, Y., Niikawa, N., Ishikawa, T. Earwax, osmidrosis, and breast cancer: why does one SNP (538G>A) in the human ABC transporter ABCC11 gene determine earwax type?

Key Words: endoplasmic reticulum-associated degradation • genetic polymorphism • N-linked glycosylation • protein instability