ABCC11

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Species	Human	Mouse
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ATP-binding cassette transporter sub-family C member 11 is a protein that in humans is encoded by the ABCC11 gene.

The gene is responsible for determination of human cerumen type (wet or dry ear wax) and presence of underarm osmidrosis (odor associated with sweat caused by excessive apocrine secretion).

Function

The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This ABC full transporter is a member of the MRP subfamily which is involved in multi-drug resistance. The product of this gene participates in physiological processes involving bile acids, conjugated steroids, and cyclic nucleotides. In addition, an SNP in this gene is responsible for determination of human earwax type and presence of underarm odour. This gene and family member ABCC12 are determined to be derived by duplication and are both localized to chromosome 16q12.1. Multiple alternatively spliced transcript variants have been described for this gene.

Molecular genetics

The ABCC11 gene is present in the human genome as two alleles, differing in one nucleotide also known as a single nucleotide polymorphism (SNP). A SNP in the ABCC11 gene on chromosome 16 at base position 538 of either a guanine or adenine controls for multiple distinct phenotypes. These respectively code for glycine and arginine in the gene's protein product. Dominant inheritance of the GG or GA genotype is observed while the AA genotype is recessive. The phenotypes expressed by the genotypes include cerumen type (wet or dry ear wax), osmidrosis (odor associated with sweat caused by excessive apocrine secretion), and breast cancer risk, although there is ongoing debate on whether if there is a real correlation of the wet ear wax phenotype to breast cancer susceptibility. The GG or GA genotype produces the wet ear wax phenotype (sticky and brown colored) and acrid sweat odor and is the dominant allele. Note this phenotype requires only the presence of one guanine. The homozygous recessive AA genotype produces the dry ear wax phenotype (dry and flaky) and mildly odored sweat.

The alleles containing a guanine produce a protein that is glycosylated but alleles containing an adenine are not glycosylated. The resulting protein is only partially degraded by proteasomes. This effect is localized to ceruminous gland membranes. Because the adenine containing allele protein product is only partially degraded, the remaining functional protein is located on the cell surface membrane which ABCC11 gene's role in sweat odor is likely in part due to the quantitative dosage of ABCC11 protein.

From an evolutionary perspective, the implications of cerumen type on fitness are unknown although odorless sweat in ancient Northern Eurasian populations have been postulated to have an adaptive advantage for cold weather. In some nonhuman mammals, mating signals via release of an odor enhanced by increased apocrine secretion may be a factor in sexual selection.

Physical human traits that are controlled by a single gene are uncommon. Most human characteristics are controlled by multiple genes (polygenes) although ABCC11 is a peculiar example of a gene with unambiguous phenotypes that is controlled by a SNP. Additionally, it is considered a pleiotropic gene.

Demographics

File:World map ABCC11 A Allele.svg

World map of the distribution of the A allele of the single nucleotide polymorphism rs17822931 in the ABCC11 gene. The proportion of A alleles in each population is represented by the white area in each circle.

The history of the migration of humans can be traced back using the ABCC11 gene alleles. The variation between ear wax and body odor in ethnicities around the world are specifically due to the ABCC11 gene alleles. It is hypothesized that 40,000 years ago, an ancient Mongoloid tribe evolved the dry ear wax phenotype that followed a spread of the dry ear wax allele to other regions of Asia via migration of the ancient tribe. The gene spread as a result of it being a beneficial adaption or through an evolutionary neutral mutation mechanism that went through genetic drift events.

The frequency of alleles for dry ear wax and odorless sweat is most concentrated in East- and Northeast Asia, most notably Korea, China, Mongolia, and western Japan. Conversely the frequency of the allele for wet ear wax and odored sweat are highest in African-American and sub-saharan populations. A downward gradient of dry ear wax allele phenotypes can be drawn from northern China to southern Asia and a east-west gradient can also be drawn from eastern Siberia to western Europe. The allele frequencies within ethnicities continued to be maintained because the ABCC11 gene is inherited as a haplotype, a group of genes or alleles that tend to be inherited as a single unit

The amount of volatile organic compounds (VOCs) in ear wax was found to be related to variation in ABCC11 genotype, which in turn is dependent on ethnic origin. In particular, the rs17822931 genotype, which is especially prevalent in East Asians, is correlated with lower VOC levels.

See also

• ATP-binding cassette transporter

References

Sources

• This article incorporates text from the United States National Library of Medicine, which is in the public domain.

Further reading

• Bera TK, Lee S, Salvatore G, Lee B, Pastan I (Aug 2001). "MRP8, a new member of ABC transporter superfamily, identified by EST database mining and gene prediction program, is highly expressed in breast cancer". Molecular Medicine. 7 (8): 509–16. PMC 1950066. PMID 11591886.
• Yabuuchi H, Shimizu H, Takayanagi S, Ishikawa T (Nov 2001). "Multiple splicing variants of two new human ATP-binding cassette transporters, ABCC11 and ABCC12". Biochemical and Biophysical Research Communications. 288 (4): 933–9. doi:10.1006/bbrc.2001.5865. PMID 11688999.
• Lai L, Tan TM (Feb 2002). "Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)-mediated efflux of cAMP and resistance to purine analogues". The Biochemical Journal. 361 (Pt 3): 497–503. doi:10.1042/0264-6021:3610497. PMC 1222332. PMID 11802779.
• Stríz I, Jaresová M, Lácha J, Sedlácek J, Vítko S (2002). "MRP 8/14 and procalcitonin serum levels in organ transplantations". Annals of Transplantation. 6 (2): 6–9. PMID 11803621.
• Tomita H, Yamada K, Ghadami M, Ogura T, Yanai Y, Nakatomi K, Sadamatsu M, Masui A, Kato N, Niikawa N (Jun 2002). "Mapping of the wet/dry earwax locus to the pericentromeric region of chromosome 16". Lancet. 359 (9322): 2000–2. doi:10.1016/S0140-6736(02)08835-9. PMID 12076558.
• Turriziani O, Schuetz JD, Focher F, Scagnolari C, Sampath J, Adachi M, Bambacioni F, Riva E, Antonelli G (Nov 2002). "Impaired 2',3'-dideoxy-3'-thiacytidine accumulation in T-lymphoblastoid cells as a mechanism of acquired resistance independent of multidrug resistant protein 4 with a possible role for ATP-binding cassette C11". The Biochemical Journal. 368 (Pt 1): 325–32. doi:10.1042/BJ20020494. PMC 1222956. PMID 12133003.
• Guo Y, Kotova E, Chen ZS, Lee K, Hopper-Borge E, Belinsky MG, Kruh GD (Aug 2003). "MRP8, ATP-binding cassette C11 (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2',3'-dideoxycytidine and 9'-(2'-phosphonylmethoxyethyl)adenine". The Journal of Biological Chemistry. 278 (32): 29509–14. doi:10.1074/jbc.M304059200. PMID 12764137.
• Bouma G, Lam-Tse WK, Wierenga-Wolf AF, Drexhage HA, Versnel MA (Aug 2004). "Increased serum levels of MRP-8/14 in type 1 diabetes induce an increased expression of CD11b and an enhanced adhesion of circulating monocytes to fibronectin". Diabetes. 53 (8): 1979–86. doi:10.2337/diabetes.53.8.1979. PMID 15277376.
• Vogl T, Ludwig S, Goebeler M, Strey A, Thorey IS, Reichelt R, Foell D, Gerke V, Manitz MP, Nacken W, Werner S, Sorg C, Roth J (Dec 2004). "MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes". Blood. 104 (13): 4260–8. doi:10.1182/blood-2004-02-0446. PMID 15331440.
• Chen ZS, Guo Y, Belinsky MG, Kotova E, Kruh GD (Feb 2005). "Transport of bile acids, sulfated steroids, estradiol 17-beta-D-glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11)". Molecular Pharmacology. 67 (2): 545–57. doi:10.1124/mol.104.007138. PMID 15537867.
• Bortfeld M, Rius M, König J, Herold-Mende C, Nies AT, Keppler D (2006). "Human multidrug resistance protein 8 (MRP8/ABCC11), an apical efflux pump for steroid sulfates, is an axonal protein of the CNS and peripheral nervous system". Neuroscience. 137 (4): 1247–57. doi:10.1016/j.neuroscience.2005.10.025. PMID 16359813.
• Viemann D, Barczyk K, Vogl T, Fischer U, Sunderkötter C, Schulze-Osthoff K, Roth J (Mar 2007). "MRP8/MRP14 impairs endothelial integrity and induces a caspase-dependent and -independent cell death program". Blood. 109 (6): 2453–60. doi:10.1182/blood-2006-08-040444. PMID 17095618.

External links

• ABCC11+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
• Human ABCC11 genome location and ABCC11 gene details page in the UCSC Genome Browser.