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Online Mendelian Inheritance in Man (OMIM)

  • ️Mon Nov 22 2010

* 607040

ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 11; ABCC11

Alternative titles; symbols

MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 8; MRP8

HGNC Approved Gene Symbol: ABCC11

Cytogenetic location: 16q12.1 Genomic coordinates (GRCh38) : 16:48,164,819-48,247,539 (from NCBI)

Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number 		Inheritance Phenotype
mapping key
16q12.1 [Axillary odor, variation in] 117800 Autosomal dominant 3
[Colostrum secretion, variation in] 117800 Autosomal dominant 3
[Earwax, wet/dry] 117800 Autosomal dominant 3

TEXT

Cloning and Expression

Tammur et al. (2001) identified ABCC11 and ABCC12 (607041) by database analysis using ABC transporter sequences as queries. The deduced 1,382-amino acid ABCC11 protein contains 2 ATP-binding domains and 2 transmembrane regions. It shares 40%, 33%, 32%, and 32% amino acid sequence identity with ABCC5 (605251), ABCC4 (605250), ABCC2 (601107), and ABCC3 (604323), respectively. PCR of a 16-tissue panel revealed expression in all tissues examined except kidney, spleen, and colon. The author determined that a second PCR product identified in lung was a splice variant lacking exon 9.

Bera et al. (2001) identified ABCC11, which they called MRP8, as a gene expressed in breast cancer tissues, and they cloned a full-length cDNA from a normal breast cDNA library. The deduced 1,382-amino acid protein has a calculated molecular mass of about 150 kD and contains 2 conserved nucleotide-binding domains and 12 putative transmembrane domains. Dot blot analysis and PCR with multiple tissues showed strong expression in testis and breast, with weaker expression in liver, prostate, placenta, and adult and fetal brain. Northern blot analysis revealed a 4.5-kb transcript expressed in breast tissue and a 4.1-kb transcript expressed in testis and liver. Sequence analysis of the shorter transcript indicated that it encodes a deduced 1,064-amino acid protein. In vitro translation revealed a 150-kD protein synthesized by the longer transcript and a 120-kD protein synthesized by the shorter transcript.

Yabuuchi et al. (2001) cloned ABCC11 from an adult liver cDNA library after identifying the putative ABC transporter by database analysis of a BAC clone. The deduced 1,383-amino acid protein shares about 47% identity with ABCC12. PCR analysis indicated wide expression in various adult and fetal tissues. They also identified a variant, which they designated variant A, in which exon 28 is entirely deleted. Variant A encodes a deduced 1,344-amino acid protein that contains 12 membrane-spanning domains, like ABCC11, but lacks 38 residues in the second ATP-binding cassette. Sequence analysis of several clones indicated that variant A is expressed at a frequency of about 25%.

Gene Structure

Tammur et al. (2001) determined that the ABCC11 gene contains 29 exons. They found that ABCC11 and ABCC12 were located tandemly, separated by about 200 kb, with the 5-prime ends facing the centromere.

Bera et al. (2001) determined that the ABCC11 gene contains 31 exons and spans more than 80.4 kb. The breast-specific variant uses all 31 exons, while the variant expressed in testis uses 26 exons and begins at an alternate transcription start site.

Yabuuchi et al. (2001) determined that the ABCC11 gene contains 30 exons spanning 68 kb and that the separation between the ABCC11 and ABCC12 genes is about 20 kb.

Mapping

Tammur et al. (2001) mapped the ABCC11 gene to chromosome 16q12.1 by radiation hybrid analysis. They noted that the ABCC11 and ABCC12 genes are contained within a BAC clone mapping to 16q12.1. Tammur et al. (2001) stated that the chromosomal localization, potential function, and expression profiles of the ABCC11 and ABCC12 genes make them promising candidates for paroxysmal kinesigenic choreoathetosis (PKC; 128200) and infantile convulsions with paroxysmal choreoathetosis (ICCA; 602066).

Molecular Genetics

Wet or dry ear wax is a mendelian trait (see 117800). Tomita et al. (2002) mapped a wet/dry ear wax locus to the pericentromeric region of chromosome 16. Yoshiura et al. (2006) undertook further mapping of the ear wax locus by performing a genotyping and case-control study of 64 Japanese individuals with dry ear wax and 54 with the wet type using 134 CA repeat markers. This led to the identification of a nonsynonymous SNP (rs17822931) in exon 4 of the ABCC11 gene (538G-A, G180R; 607040.0001), which showed close association with the ear wax type. In a new series of 126 Japanese individuals, 87 of 88 individuals with dry ear wax were AA homozygotes, and all 38 individuals with the wet type were either GA heterozygotes or GG homozygotes, consistent with the previous conclusions that the wet cerumen phenotype is completely dominant to the dry type. By a functional assay, Yoshiura et al. (2006) demonstrated that cells with allele A show a lower excretory activity for cGMP than those with allele G. A 27-bp deletion in ABCC11 exon 29 (607040.0002) was also found in a few individuals with Asian ancestry.

By genotyping 225 Japanese women for the rs17822931 SNP in the ABCC11 gene, Miura et al. (2007) reported an association between ear wax type and apocrine colostrum secretion (see 117800) from the mammary gland on the first postpartum day. The absence of colostrum secretion was more common among women with dry ear wax (105 of 155, 67.7%) compared to women with wet ear wax (28 of 70, 40%). The authors noted that both colostrum and cerumen have a common origin in the secretory glands and suggested that the ABCC11 gene product may play a role in colostrum secretion independent of endocrine control.

Dry ear wax has been associated with reduced axillary odor (Matsunaga, 1962). In 18 Asian and 7 Caucasian individuals, Martin et al. (2010) determined the ABCC11 538G-A genotype and demonstrated that in AA homozygotes, the secretion of amino-acid conjugates of human-specific odorants was abolished and the secretion of steroidal odorants and their putative precursors were significantly reduced. Martin et al. (2010) concluded that ABCC11 plays a key role in the secretion of odorants and their precursors from apocrine sweat glands.

Population Genetics

In the study of Yoshiura et al. (2006), frequency of the A allele of the 538G-A polymorphism showed a north-south and east-west downward geographic gradient; worldwide, it was highest in Chinese and Koreans, and a common dry-type haplotype was retained among various ethnic populations. These results suggested that the allele A arose in northeast Asia and thereafter spread through the world.

The aboriginal Ainu population of the Japanese island of Hokkaido has an exceptionally high frequency of the dominant wet ear wax phenotype compared to those of neighboring Asian populations (see Yoshiura et al., 2006). Sato et al. (2009) genotyped specimens from various Okhotsk and Jomon/Epi-Jomon archaeologic sites on Hokkaido for rs17822931. Analysis of 31 specimens of the Okhotsk people and 19 specimens of the Jomon/Epi-Jomon people showed that the frequency of the wet-type allele was higher among the Jomon/Epi-Jomon compared to other northeastern Asian populations, including even modern Ainu. In contrast, the Okhotsk had relatively higher frequencies of the dry-type allele compared to Ainu and Jomon/Epi-Jomon. The findings suggested that gene flow occurred from northeastern Asia to descendants of the Jomon/Epi-Jomon through the Okhotsk, resulting in the establishment of the Ainu.

ALLELIC VARIANTS 2 Selected Examples):

.0001   APOCRINE GLAND SECRETION, VARIATION IN

EAR WAX, WET/DRY, INCLUDED
AXILLARY ODOR, INCLUDED
COLOSTRUM SECRETION, INCLUDED

ABCC11, GLY180ARG ({dbSNP rs17822931})
SNP: rs17822931, gnomAD: rs17822931, ClinVar: RCV000003737, RCV000003738, RCV000003739, RCV004714398

The wet cerumen phenotype is completely dominant to the dry type (see 117800). Yoshiura et al. (2006) demonstrated that the dry ear wax phenotype is recessive due to homozygous state of a 538G-A transition in exon 4 of the ABCC11 gene (rs17822931), predicting a gly180-to-arg (G180R) amino acid substitution. The AA genotype corresponds to dry ear wax, and GA and GG to the wet type.

By genotyping 225 Japanese women for the rs17822931 SNP in the ABCC11 gene, Miura et al. (2007) reported an association between ear wax type and apocrine colostrum secretion (see 117800) from the mammary gland on the first postpartum day. The absence of colostrum secretion was more common among women with dry ear wax (105 of 155, 67.7%) compared to women with wet ear wax (28 of 70, 40%). The authors noted that both colostrum and cerumen have a common origin in the secretory glands and suggested that the ABCC11 gene product may play a role in colostrum secretion independent of endocrine control.

Martin et al. (2010) performed chemical analysis of axillary sweat samples from 25 individuals with different ABCC11 538G-A genotypes, including 18 Asian participants (11 AA homozygotes, 5 AG heterozygotes, and 2 GG homozygotes) and 7 Caucasian participants (2 AG heterozygotes and 5 GG homozygotes). Levels of 3 glutamine conjugates that are precursors for key body odorants were below detection limits in all participants with the AA genotype but were present in all AG and GG individuals, indicating that ABCC11 is essential for secretion of amino-acid conjugates of relevant axillary odors (see 117800). RT-PCR analysis of armpit and face skin showed that ABCC11 was expressed only in the armpit specimens, suggesting that ABCC11 expression is specific to tissue containing apocrine sweat glands. Similarly, cDNA microarray analysis demonstrated 1.63-fold upregulation of ABCC11 expression in apocrine sweat glands versus 21.40-fold downregulation in eccrine sweat glands compared to a common reference. Immunohistochemistry revealed that the ABCC11 signal was concentrated in the same parts of apocrine glands in both AA and GG homozygotes, indicating that the nonfunctional ABCC11 protein is still translocated to its site of action.

.0002   APOCRINE GLAND SECRETION, VARIATION IN

EAR WAX, WET/DRY, INCLUDED

ABCC11, 27-BP DEL
SNP: rs387906296, gnomAD: rs387906296, ClinVar: RCV000003740

Yoshiura et al. (2006) found that a 27-bp deletion in ABCC11 exon 29 was associated with the dry type of cerumen (see 117800) in a few individuals of Asian ancestry.

REFERENCES

  1. Bera, T. K., Lee, S., Salvatore, G., Lee, B., Pastan, I. MRP8, a new member of ABC transporter superfamily, identified by EST database mining and gene prediction program, is highly expressed in breast cancer. Molec. Med. 7: 509-516, 2001. [PubMed: 11591886]

  2. Martin, A., Saathoff, M., Kuhn, F., Max, H., Terstegen, L., Natsch, A. A functional ABCC11 allele is essential in the biochemical formation of human axillary odor. J. Invest. Derm. 130: 529-540, 2010. [PubMed: 19710689] [Full Text: https://doi.org/10.1038/jid.2009.254]

  3. Matsunaga, E. The dimorphism in human normal cerumen. Ann. Hum. Genet. 25: 273-286, 1962. [PubMed: 14471313] [Full Text: https://doi.org/10.1111/j.1469-1809.1962.tb01766.x]

  4. Miura, K., Yoshiura, K., Miura, S., Shimada, T., Yamasaki, K., Yoshida, A., Nakayama, D., Shibata, Y., Niikawa, N., Masuzaki, H. A strong association between human earwax-type and apocrine colostrum secretion from the mammary gland. Hum. Genet. 121: 631-633, 2007. [PubMed: 17394018] [Full Text: https://doi.org/10.1007/s00439-007-0356-9]

  5. Sato, T., Amano, T., Ono, H., Ishida, H., Kodera, H., Matsumura, H., Yoneda, M., Masuda, R. Allele frequencies of the ABCC11 gene for earwax phenotypes among ancient populations of Hokkaido, Japan. J. Hum. Genet. 54: 409-413, 2009. [PubMed: 19557017] [Full Text: https://doi.org/10.1038/jhg.2009.56]

  6. Tammur, J., Prades, C., Arnould, I., Rzhetsky, A., Hutchinson, A., Adachi, M., Schuetz, J. D., Swoboda, K. J., Ptacek, L. J., Rosier, M., Dean, M., Allikmets, R. Two new genes from the human ATP-binding cassette transporter superfamily, ABCC11 and ABCC12, tandemly duplicated on chromosome 16q12. Gene 273: 89-96, 2001. [PubMed: 11483364] [Full Text: https://doi.org/10.1016/s0378-1119(01)00572-8]

  7. Tomita, H., Yamada, K., Ghadami, M., Ogura, T., Yanai, Y., Nakatomi, K., Sadamatsu, M., Masui, A., Kato, N., Niikawa, N. Mapping of the wet/dry earwax locus to the pericentromeric region of chromosome 16. Lancet 359: 2000-2002, 2002. [PubMed: 12076558] [Full Text: https://doi.org/10.1016/S0140-6736(02)08835-9]

  8. Yabuuchi, H., Shimizu, H., Takayanagi, S., Ishikawa, T. Multiple splicing variants of two new human ATP-binding cassette transporters, ABCC11 and ABCC12. Biochem. Biophys. Res. Commun. 288: 933-939, 2001. [PubMed: 11688999] [Full Text: https://doi.org/10.1006/bbrc.2001.5865]

  9. Yoshiura, K., Kinoshita, A., Ishida, T., Ninokata, A., Ishikawa, T., Kaname, T., Bannai, M., Tokunaga, K., Sonoda, S., Komaki, R., Ihara, M., Saenko, V. A., and 27 others. A SNP in the ABCC11 gene is the determinant of human earwax type. Nature Genet. 38: 324-330, 2006. [PubMed: 16444273] [Full Text: https://doi.org/10.1038/ng1733]

Contributors:

Marla J. F. O'Neill - updated : 11/22/2010
Cassandra L. Kniffin - updated : 1/7/2010
Cassandra L. Kniffin - updated : 6/6/2007
Victor A. McKusick - updated : 2/24/2006

Creation Date:

Patricia A. Hartz : 6/17/2002

Edit History:

carol : 10/18/2016
wwang : 02/28/2011
wwang : 11/23/2010
terry : 11/22/2010
wwang : 1/22/2010
ckniffin : 1/7/2010
wwang : 6/14/2007
ckniffin : 6/6/2007
alopez : 3/1/2006
alopez : 3/1/2006
terry : 2/24/2006
mgross : 6/17/2002