Copy number variations of the ATP-binding cassette transporter ABCC6 gene and its pseudogenes

BMC Research Notes

Armin P Piehler²  Jens P Berg¹  Runa M Grimholt¹  Camilla Stormo¹  Marianne K Kringen³ 

[1] Department of Medical Biochemistry, Oslo University Hospital, Ullevål, P.O. Box 4956, Nydalen, 0424 Oslo, Norway;Furst Medical Laboratory, Søren Bullsvei 25, 1051 Oslo, Norway;Department of Pharmacology, Oslo University Hospital, Ullevål, P.O. Box 4956, Nydalen, 0424 Oslo, Norway

关键词: Transcription;    Pyrosequencing;    Pseudogenes;    ABCC6;    Copy number variation;   

Others  :  1165968
DOI  :  10.1186/1756-0500-5-425

 received in 2012-02-24, accepted in 2012-08-01,  发布年份 2012

【 摘 要 】

Background

The ATP-binding cassette transporter ABCC6 gene is located on chromosome 16 between its two pseudogenes (ABCC6P1 and ABCC6P2). Previously, we have shown that ABCC6P1 is transcribed and affects ABCC6 at the transcriptional level. In this study we aimed to determine copy number variations of ABCC6, ABCC6P1 and ABCC6P2 in different populations. Moreover, we sought to study the transcription pattern of ABCC6 and ABCC6 pseudogenes in 39 different human tissues.

Findings

Genomic DNA from healthy individuals from five populations, Chinese (n = 24), Middle East (n = 20), Mexicans (n = 24), Caucasians (n = 50) and Africans (n = 24), were examined for copy number variations of ABCC6 and its pseudogenes by pyrosequencing and quantitative PCR. Copy number variation of ABCC6 was very rare (2/142; 1.4%). However, one or three copies of ABCC6P1 were relatively common (3% and 8%, respectively). Only one person had a single copy of ABCC6P2 while none had three copies. In Chinese, deletions or duplications of ABCC6P1 were more frequent than in any other population (9/24; 37.5%). The transcription pattern of ABCC6P2 was highly similar to ABCC6 and ABCC6P1, with highest transcription in liver and kidney. Interestingly, the total transcription level of pseudogenes, ABCC6P1 + ABCC6P2, was higher than ABCC6 in most tissues, including liver and kidney.

Conclusions

Copy number variations of the ABCC6 pseudogenes are quite common, especially in populations of Chinese ancestry. The expression pattern of ABCC6P2 in 39 human tissues was highly similar to that of ABCC6 and ABCC6P1 suggesting similar regulatory mechanisms for ABCC6 and its pseudogenes.

【 授权许可】

   
2012 Kringen et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Higgins CF: ABC transporters: from microorganisms to man. Annu Rev Cell Biol 1992, 8:67-113.
• [2]Holland IB, Cole SPC, Kuchler K, Higgins CF: ABC Proteins: From Bacteria to Man. 1st edition. Academic Press, London; 2002.
• [3]Pulkkinen L, Nakano A, Ringpfeil F, Uitto J: Identification of ABCC6 pseudogenes on human chromosome 16p: implications for mutation detection in pseudoxanthoma elasticum. Hum Genet 2001, 109:356-365.
• [4]Mighell AJ, Smith NR, Robinson PA, Markham AF: Vertebrate pseudogenes. FEBS Lett 2000, 468:109-114.
• [5]Balakirev ES, Ayala FJ: Pseudogenes: are they “junk” or functional DNA? Annu Rev Genet 2003, 37:123-151.
• [6]Aranyi T, Ratajewski M, Bardoczy V, Pulaski L, Bors A, Tordai A, et al.: Identification of a DNA methylation-dependent activator sequence in the pseudoxanthoma elasticum gene, ABCC6. J Biol Chem 2005, 280:18643-18650.
• [7]Piehler AP, Hellum M, Wenzel JJ, Kaminski E, Haug KB, Kierulf P, et al.: The human ABC transporter pseudogene family: Evidence for transcription and gene-pseudogene interference. BMC Genomics 2008, 9:165. BioMed Central Full Text
• [8]Costrop LM, Vanakker OO, Van LL, Le SO, Martin L, Chassaing N, et al.: Novel deletions causing pseudoxanthoma elasticum underscore the genomic instability of the ABCC6 region. J Hum Genet 2010, 55:112-117.
• [9]Uitto J, Li Q, Jiang Q: Pseudoxanthoma elasticum: molecular genetics and putative pathomechanisms. J Invest Dermatol 2010, 130:661-670.
• [10]Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA, et al.: Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet 2006, 38:1038-1042.
• [11]Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, et al.: Global variation in copy number in the human genome. Nature 2006, 444:444-454.
• [12]Ahmadian A, Gharizadeh B, Gustafsson AC, Sterky F, Nyren P, Uhlen M, et al.: Single-nucleotide polymorphism analysis by pyrosequencing. Anal Biochem 2000, 280:103-110.
• [13]Bailey JA, Gu Z, Clark RA, Reinert K, Samonte RV, Schwartz S, et al.: Recent segmental duplications in the human genome. Science 2002, 297:1003-1007.
• [14]Stankiewicz P, Lupski JR: Genome architecture, rearrangements and genomic disorders. Trends Genet 2002, 18:74-82.
• [15]Symmons O, Varadi A, Aranyi T: How segmental duplications shape our genome: recent evolution of ABCC6 and PKD1 Mendelian disease genes. Mol Biol Evol 2008, 25:2601-2613.
• [16]Ratajewski M, de Boussac H, Pulaski L: Liver-specific enhancer in ABCC6 promoter-Functional evidence from natural polymorphisms. Biochem Biophys Res Commun 2009, 383:73-77.
• [17]de Boussac H, Ratajewski M, Sachrajda I, Koblos G, Tordai A, Pulaski L, et al.: The ERK1/2-hepatocyte nuclear factor 4alpha axis regulates human ABCC6 gene expression in hepatocytes. J Biol Chem 2010, 285:22800-22808.
• [18]Pink RC, Wicks K, Caley DP, Punch EK, Jacobs L, Carter DR: Pseudogenes: pseudo-functional or key regulators in health and disease? RNA 2011, 17:792-798.
• [19]Watanabe T, Totoki Y, Toyoda A, Kaneda M, Kuramochi-Miyagawa S, Obata Y, et al.: Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 2008, 453:539-543.
• [20]Tam OH, Aravin AA, Stein P, Girard A, Murchison EP, Cheloufi S, et al.: Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 2008, 453:534-538.
• [21]Piehler AP, Haug KB, Wenzel JJ, Kierulf PB, Kaminski WE: ABCA-transporters: regulators of cellular lipid transport. Tidsskr Nor Laegeforen 2007, 127:2930-2933.
• [22]Duret L, Chureau C, Samain S, Weissenbach J, Avner P: The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene. Science 2006, 312:1653-1655.
• [23]Muro EM, Mah N, Andrade-Navarro MA: Functional evidence of post-transcriptional regulation by pseudogenes. Biochimie 2011, 93:1916-1921.
• [24]Greve B, Hoffmann P, Vonthein R, Kun J, Lell B, Mycko MP, et al.: NCF1 gene and pseudogene pattern: association with parasitic infection and autoimmunity. Malar J 2008, 7:251. BioMed Central Full Text
• [25]Brunson T, Wang Q, Chambers I, Song Q: A copy number variation in human NCF1 and its pseudogenes. BMC Genet 2010, 11:13.
• [26]Olsson LM, Nerstedt A, Lindqvist AK, Johansson SC, Medstrand P, Olofsson P, et al.: Copy number variation of the gene NCF1 is associated with rheumatoid arthritis. Antioxid Redox Signal 2012, 16:71-78.
• [27]Vandesompele J, de Preter K, Pattyn F, Poppe B, van Roy N, de Paepe A, et al.: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002, 3: . RESEARCH0034
• [28]Piehler AP, Grimholt RM, Ovstebo R, Berg JP: Gene expression results in lipopolysaccharide-stimulated monocytes depend significantly on the choice of reference genes. BMC Immunol 2010, 11:21. BioMed Central Full Text