ABCC11

ABCC11
Identifiers
Aliases	ABCC11 , ATP-binding cassette, sub-family C (CFTR/MRP), member 11, EWWD, MRP8, WW, ATP binding cassette subfamily C member 11, ATP-binding cassette transporter sub-family C member 1
External IDs	OMIM: 607040; HomoloGene: 69511; GeneCards: ABCC11; OMA:ABCC11 - orthologs
Gene location (Human) Chr. Chromosome 16 (human) [1] Band 16q12.1 Start 48,165,773 bp [1] End 48,247,568 bp [1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver right uterine tube sural nerve prefrontal cortex lactiferous duct putamen nucleus accumbens amygdala caudate nucleus stromal cell of endometrium n/a More reference expression data BioGPS n/a
Gene ontology Molecular function nucleotide binding organic anion transmembrane transporter activity ATPase activity ATP binding purine nucleotide transmembrane transporter activity ATPase-coupled inorganic anion transmembrane transporter activity ATPase-coupled transmembrane transporter activity Cellular component integral component of membrane integral component of plasma membrane extracellular exosome membrane vacuole vacuolar membrane plasma membrane cytoplasmic vesicle membrane cytoplasmic vesicle Biological process purine nucleotide transport transmembrane transport organic anion transport transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 85320 n/a Ensembl ENSG00000121270 n/a UniProt Q96J66 n/a RefSeq (mRNA) NM_032583 NM_033151 NM_145186 NM_001370496 NM_001370497 n/a RefSeq (protein) NP_115972 NP_149163 NP_660187 NP_001357425 NP_001357426 NP_115972.2 NP_149163.2 n/a Location (UCSC) Chr 16: 48.17 – 48.25 Mb n/a PubMed search [2] n/a
Wikidata
View/Edit Human

ATP-binding cassette transporter sub-family C member 11, also MRP8 (Multidrug Resistance-Related Protein 8), is a membrane transporter that exports certain molecules from inside a cell. It is a protein that in humans is encoded by gene ABCC11. ^{[3] [4] [5]}

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 apocrine secretion), and is associated with colostrum secretion. ^[6]

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). The ABCC11 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, a single nucleotide polymorphism (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. ^[5]

Molecular genetics

Location of ABCC11 with its 30 exons on chromosome 16. The important single nucleotide polymorphism (SNP) 538G → A is located on exon 4.

The ABCC11 gene is present in the human genome as two alleles, differing in one nucleotide also known as a single nucleotide polymorphism (SNP). ^[7] A SNP in the ABCC11 gene on chromosome 16 at base position 538 of either a guanine or adenine determines two distinct groups of phenotypes. ^{[7] [8]} 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 possibly breast cancer risk, although there is ongoing debate on whether there is a real correlation of the wet ear wax phenotype to breast cancer susceptibility. ^{[9] [10]} The GG or GA genotype produces the wet ear wax phenotype (sticky and brown colored) and acrid sweat odor and is the dominant allele. ^[9] 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. ^[9]

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. ^[7] This effect is localized to ceruminous gland membranes. ^[7] 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. ^[7]

From an evolutionary perspective, the implications of cerumen type on fitness are unknown. However, odorless sweat in ancient Northern Eurasian populations has been postulated to have an adaptive advantage for cold weather. ^[8] In some nonhuman mammals, mating signals via release of an odor enhanced by increased apocrine secretion may be a factor in sexual selection. ^[8]

Physical human traits that are controlled by a single gene are uncommon. Most human characteristics are controlled by multiple genes (polygenes); 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

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 in ethnicities around the world are specifically due to the ABCC11 gene alleles. ^[8] It is believed that the derived allele originated in an ancient East Asian population. ^[11] The gene may have spread as a result of it being a beneficial adaption or through an evolutionary neutral mutation mechanism that went through genetic drift events, or through sexual selection. ^[12]

An analysis of ancient DNA of Eastern European hunter gatherers, Scandinavian Hunter Gatherers, Western Hunter Gatherers and Early European Farmers. The study found that the derived allele of ABCC11 associated with dry earwax and reduced body odor was absent in all European hunter gatherers, except for a Western Hunter Gatherer from Mesolithic central Europe. The derived allele was absent in the paleolithic hunter gatherer Kostenki 14, who is deeply related to Ancient North Eurasians. ^[13]

The frequency of alleles for dry ear wax is most concentrated in East Asia; most notably Korea, China, Mongolia, and Japan. The allele frequency is highest among the northern Han Chinese and Koreans; followed by Mongolians, southern Han Chinese, and Yamato Japanese, respectively. The frequency is low among the Ryukyuans and Ainu. ^[8] The derived allele is not rare in South Asia, with 54% of Dravidian people from Tamil Nadu carrying an AA genotype. ^[8] A downward gradient of dry ear wax allele phenotypes can be drawn from northern China to southern Asia and an east–west gradient can also be drawn from eastern Siberia to western Europe. ^[8] 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. ^{[8] [14]}

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. However, VOC levels were not found to vary significantly qualitatively nor quantitatively for most organic compounds by racial group after Bonferroni corrections, suggesting that it does not result in ethnic differences. ^[15]

See also

• ATP-binding cassette transporter
• Body odor

References

Citations

1. GRCh38: Ensembl release 89: ENSG00000121270 – Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. Tammur J, Prades C, Arnould I, Rzhetsky A, Hutchinson A, Adachi M, et al. (Jul 2001). "Two new genes from the human ATP-binding cassette transporter superfamily, ABCC11 and ABCC12, tandemly duplicated on chromosome 16q12". Gene. 273 (1): 89–96. doi:10.1016/S0378-1119(01)00572-8. PMID   11483364.
4. Dean M, Rzhetsky A, Allikmets R (Jul 2001). "The human ATP-binding cassette (ABC) transporter superfamily". Genome Research. 11 (7): 1156–66. doi: 10.1101/gr.184901 . PMID   11435397. S2CID   9528197.
5. "Entrez Gene: ABCC11 ATP-binding cassette, sub-family C (CFTR/MRP), member 11".
6. Miura K, Yoshiura Ki, Miura S, Shimada T, Yamasaki K, Yoshida A, et al. (June 2007). "A strong association between human earwax-type and apocrine colostrum secretion from the mammary gland". Human Genetics. 121 (5): 631–633. doi:10.1007/s00439-007-0356-9. ISSN   0340-6717. PMID   17394018. S2CID   575882.
7. Toyoda Y, Sakurai A, Mitani Y, Nakashima M, Yoshiura K, Nakagawa H, et al. (Jun 2009). "Earwax, osmidrosis, and breast cancer: why does one SNP (538G>A) in the human ABC transporter ABCC11 gene determine earwax type?". FASEB Journal. 23 (6): 2001–13. doi: 10.1096/fj.09-129098 . PMID   19383836. S2CID   26853548.
8. Yoshiura K, Kinoshita A, Ishida T, Ninokata A, Ishikawa T, Kaname T, et al. (Mar 2006). "A SNP in the ABCC11 gene is the determinant of human earwax type". Nature Genetics. 38 (3): 324–30. doi:10.1038/ng1733. PMID   16444273. S2CID   3201966.
9. Rodriguez S, Steer CD, Farrow A, Golding J, Day IN (Jul 2013). "Dependence of deodorant usage on ABCC11 genotype: scope for personalized genetics in personal hygiene". The Journal of Investigative Dermatology. 133 (7): 1760–7. doi:10.1038/jid.2012.480. PMC   3674910 . PMID   23325016.
10. Park YJ, Shin MS (Sep 2001). "What is the best method for treating osmidrosis?". Annals of Plastic Surgery. 47 (3): 303–9. doi:10.1097/00000637-200109000-00014. PMID   11562036. S2CID   25590802.
11. Hori YS, Yamada A, Matsuda N, Ono Y, Starenki D, Sosonkina N, et al. (2017). "A Novel Association between the 27-bp Deletion and 538G>A Mutation in the ABCC11 Gene". Human Biology. 89 (4): 305–307. doi:10.13110/humanbiology.89.4.04. ISSN   1534-6617. PMID   30047321. S2CID   51721105. "were highest in East Asia, with decreasing frequencies observed toward Europe and Southern Asia, suggesting an East Asian origin."
12. Martin A, Saathoff M, Kuhn F, Max H, Terstegen L, Natsch A (February 2010). "A functional ABCC11 allele is essential in the biochemical formation of human axillary odor". The Journal of Investigative Dermatology. 130 (2): 529–540. doi: 10.1038/jid.2009.254 . PMID   19710689. S2CID   36754463.
13. Günther T, Malmström H, Svensson EM (January 2018). "Population genomics of Mesolithic Scandinavia: Investigating early postglacial migration routes and high-latitude adaptation". PLOS Biology. 16 (1): e2003703. doi: 10.1371/journal.pbio.2003703 . PMC   5760011 . PMID   29315301. From Supporting Information file S8, page 17/28: "Furthermore, SF9, SBj, Hum2 and SF12 as well as all other HG tested (with the exception of KO1), carried allelic variants at ABCC1 gene associated with wet earwax, normal body odor and normal colostrum [69]." See also: Supporting Information File S1
14. Prokop-Prigge KA, Mansfield CJ, Parker MR, Thaler E, Grice EA, Wysocki CJ, et al. (Jan 2015). "Ethnic/racial and genetic influences on cerumen odorant profiles". Journal of Chemical Ecology. 41 (1): 67–74. Bibcode:2015JCEco..41...67P. doi:10.1007/s10886-014-0533-y. PMC   4304888 . PMID   25501636.
15. Prokop-Prigge KA, Greene K, Varallo L, Wysocki CJ, Preti G (2016). "The Effect of Ethnicity on Human Axillary Odorant Production". Journal of Chemical Ecology. 42 (1): 33–9. Bibcode:2016JCEco..42...33P. doi:10.1007/s10886-015-0657-8. PMC   4724538 . PMID   26634572.

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. doi:10.1007/BF03401856. 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, et al. (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. S2CID   20226277.
• Turriziani O, Schuetz JD, Focher F, Scagnolari C, Sampath J, Adachi M, et al. (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, et al. (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. S2CID   6081066.
• 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 . hdl: 1765/10354 . PMID   15277376.
• Vogl T, Ludwig S, Goebeler M, Strey A, Thorey IS, Reichelt R, et al. (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. S2CID   5407110.
• 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. S2CID   18527978.
• 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. S2CID   22719472.
• Viemann D, Barczyk K, Vogl T, Fischer U, Sunderkötter C, Schulze-Osthoff K, et al. (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 U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human ABCC11 genome location and ABCC11 gene details page in the UCSC Genome Browser .