title: Earwax, osmidrosis, and breast cancer: why does one SNP (538G>A) in the human ABC transporter ABCC11 gene determine earwax type?
abstract: 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.
authors.affiliation: Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B-60 Nagatsuta, Midori-ku, Yokohama 226-8501, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Aki
authors.initials: A
authors.lastname: Sakurai
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Mitani
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nakashima
authors.forename: Koh-ichiro
authors.initials: K
authors.lastname: Yoshiura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sakai
authors.forename: Ikuko
authors.initials: I
authors.lastname: Ota
authors.forename: Alexander
authors.initials: A
authors.lastname: Lezhava
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Hayashizaki
authors.forename: Norio
authors.initials: N
authors.lastname: Niikawa
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Ishikawa
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001050:Apocrine Glands / Q000166:cytology / Q000378:metabolism; D001365:Axilla / Q000033:anatomy & histology; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002571:Cerumen / Q000737:chemistry* / Q000378:metabolism; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005838:Genotype; D006031:Glycosylation; D006801:Humans; D008969:Molecular Sequence Data; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015203:Reproducibility of Results; D016415:Sequence Alignment; D013543:Sweat Gland Diseases / Q000235:genetics*
chemical_list: C435500:ABCC11 protein, human; D018528:ATP-Binding Cassette Transporters; D000906:Antibodies; D046988:Proteasome Endopeptidase Complex