Abstract
ABCC6 belongs to the adenosine triphosphate-binding cassette (ABC) gene subfamily C. This protein family is involved in a large variety of physiological processes, such as signal transduction, protein secretion, drug and antibiotic resistance, and antigen presentation [Kool et al. (1999) 59:175–182; Borst and Elferink (2002) 71:537–592]. ABCC6 is primarily and highly expressed in the liver and kidney [Kool et al. (1999) 59:175–182; Bergen et al. (2000) 25:228–2231]. The precise physiological function and natural substrate(s) transported by ABCC6 are unknown, but the protein may be involved in active transport of intracellular compounds to the extracellular environment [Kool et al. (1999) 59:175–182] [Scheffer et al. (2002) 82:515–518]. Recently, it was shown that loss of function mutations in ABCC6 cause pseudoxanthoma elasticum (PXE) [Bergen et al. (2000) 25:228–2231; Le Saux et al. (2000) 25:223–227]. PXE is an autosomal recessively inherited multi-organ disorder [Goodman et al. (1963) 42:297–334; Lebwohl et al. (1994) 30:103–107]. PXE is primarily associated with the accumulation of mineralized and fragmented elastic fibers of the connective tissue in the skin [Neldner (1988) 6:1–159], Bruch’s membrane in the retina [Hu et al. (2003) 48:424–438], and vessel walls [Kornet et al. (2004) 30:1041–1048]. PXE patients usually have skin lesions and breaks in Bruch’s membrane of the retina (angioid streaks). Also, a variety of cardiovascular complications has been observed [Hu et al. (2003) 48:424–438]. Recently, a mouse model for PXE was created by targeted disruption of Abcc6 [Gorgels et al. (2005) 14:1763–1773; Klement et al. (2005) 25:8299–8310], which may be useful to elucidate the precise function of Abcc6 and to develop experimental therapies.
Similar content being viewed by others
ABCC6 in man: structure, function and physiological substrates
Human ABCC6, formerly called MRP6, belongs to the adenosine triphosphate (ATP)-binding cassette (ABC) gene subfamily C, together with ABCC1-13 [7, 25]. In man, ABCC6 consists of 31 exons spanning ∼73 kb genomic DNA. The ABCC6 mRNA is approximately 6 kb and has an open reading frame of 4.5 kb. The latter encodes a protein of 1503 aa. ABCC6 is composed of 17 transmembrane spanning domains and two evolutionary conserved intracellular nucleotide binding folds (NBFs). The NBFs contain conserved Walker A and B domains, and a C motif critical for ATP binding and transmembrane transporter functions [9, 21]. The putative protein structure is presented in Fig. 1.
Two ABCC6 pseudogenes have been identified, which are, respectively, homologous to exon 1 through intron 4, and exon 1 through intron 9 [8, 14].
The exact function and natural substrate(s) of ABCC6 are currently unknown. ABCC6 is highly homologous to ABCC1 (43% identity on amino acid level) [25]. For that reason, ABCC6 was classified as a multidrug resistance-associated protein. However, subsequently, Kool et al. [25] and Belinsky et al. [4] showed that the role of ABCC6 in drug resistance is limited to low-level resistance of a number of compounds, like etoposide, teniposide, doxorubicin, and daunorubicin. In vitro experiments showed that ABCC6 actively transports the glutathione S-conjugates leukotriene C(4) and S-(2, 4-dinitrophenyl) glutathione, and the cyclopentapeptide BQ123 [4, 22, 32].
ABCC6 is highly expressed in human liver and kidneys (Fig. 2) [6, 25]. Low-expression levels of ABCC6 were detected in numerous other tissues, including skin, neural retina, and vessel walls [2, 6, 25]. Using several polyclonal antibodies, ABCC6 was localized to the basolateral side of human hepatocytes and to the basolateral membranes of the proximal kidney tubules. The latter suggests that ABCC6 transports intracellular biomolecules back into the blood [45].
ABCC6 mutations cause pseudoxanthoma elasticum (PXE)
Pseudoxanthoma elasticum
The gene implicated in PXE was initially localized to a subchromosomal segment of chromosome 16 [28, 46, 50], which contained both the ABCC1 and ABCC6 genes. Subsequently, several groups showed that loss of function mutations in ABCC6 were responsible for PXE [5, 28, 29]. PXE is primarily an autosomal recessive disorder of the connective tissue, affecting the skin, eye, and the cardiovascular system (Fig. 2) [11, 37, 41, 42]. Pseudo-dominance occurs apparently frequently, due to high carrier frequency and consanguinity [41]. Also, a number of heterozygote carriers manifest mild symptoms of the disease [1]. PXE is, so far, incurable and appears to be present in all of the world’s populations, with an estimated prevalence of at least 1: 70,000 persons [9, 41].
Histopathologically, progressive mineralization and fragmentation of elastic fibers in skin, Bruch’s membrane in the retina, as well as vessel walls can be seen [11, 15, 37]. Mineralization of fragmented elastic fibers can be visualized using a Von Kossa stain [51]. The clinical expression of PXE is heterogeneous, with considerable variation in age of onset, progression, and severity, even within families [5, 20, 41]. Patients usually develop skin lesions and angioid streaks. Skin abnormalities frequently start at the side of the neck (Fig. 3) and in flexural areas such as armpits, antecubital and popliteal fossae, the inguinal region, and the periumbilical area. Skin lesions are usually ivory to yellowish-colored, raised papules of 1–3 mm. The papules may have a linear or reticular arrangement and may coalesce into plaques or larger confluent areas. In a number of PXE cases, the skin becomes wrinkled, redundant, and hangs in folds [21, 37]. Ocular disease eventually develops in all patients with PXE. The usual sequence of developing eye abnormalities is peau d’orange, angioid streaks, peripapillary atrophy, white glial tissue formation, and finally, subretinal neovascularization (Fig. 3). The latter results in disciform scarring of the macula which causes decreased visual acuity [21]. The most common cardiovascular complications in PXE are: diminished or absent peripheral vascular pulsations (in 25% of patients), early onset renovascular hypertension and echographic opacities due to calcification of arteries in kidneys, spleen, and pancreas (25%), arterial hypertension (22.5%), angina pectoris (19%), intermittent claudication (18%), and gastrointestinal hemorrhages (13%). In PXE patients, the compressibility of the carotid arterial wall was 44% higher than in control subjects, perhaps due to a higher amount of proteoglycans in the PXE vessel walls [9]. The PXE phenotype was recently extensively reviewed by Hu et al. [21].
Mutations in ABCC6 cause pseudoxanthoma elasticum
Mutations in ABCC6 are implicated in pseudoxanthoma elasticum (PXE) [6, 27, 29, 44]. Currently, at least one ABCC6 mutation is found in 90% of our patients with a clinically well-characterized PXE phenotype [19] (unpublished results). So far, approximately 100 different mutations have been reported in ABCC6 (Fig. 1, Table 1) [9, 23, 35]. The most important sequence changes are missense (55%) and nonsense (15%) mutations, as well as small deletions (15%). The remainder of pathogenic variants consists of splicing errors, larger deletions, and a number of insertions. At least 30% of all mutations cause a frameshift and the introduction of a stopcodon, which leads to premature chain termination. Most pathogenic sequence changes replace evolutionary conserved residues [9, 20, 27].
Mutations associated with PXE occur in, virtually, every exon of ABCC6. The vast majority of mutations occur in cytoplasmatic domains and the carboxy-terminal end of the ABCC6 protein. Only sporadically, pathogenic variants were found in extracellular and transmembrane domains. Mutations especially target the NBF1 and NBF2 domains, and the 8th intracellular loop [20]. The latter distribution strongly supports the critical role of NBFs in ATP-driven transport. In addition, this distribution suggests that the 8th intracellular loop is functionally important, perhaps for ABCC6 substrate recognition [9, 20, 27].
Two ABCC6 mutations, R1141X and del(ex23_29), occur very frequently, probably due to founder effects and genetic drift. R1141X accounts for up to 30% of mutations found in European populations [9, 18], but accounts for only 4% of the US PXE population. In contrast, ABCC6 del(ex23_29) is present in 28% of the US population [9, 27], and in 4% of the European one. R1141X probably produces an instable ABCC6 mRNA which is rapidly degraded by nonsense mediated RNA decay [18, 29]. Finally, R1141X may be associated with premature coronary artery disease [48].
ABCC6 and PXE in man: expression, protein distribution, pathology
Currently, the mainstream hypothesis is that PXE is a systemic disorder, caused by ABCC6 defects in the liver and kidney (Fig. 2) [49]. However, the alternative hypothesis is that PXE is a local, peripheral defect, and that ABCC6 defects play a direct role at the sites of pathology [38–40, 43]. Obviously, these hypotheses are not mutually exclusive.
How does ABCC6 gene expression and protein localization in man relate to PXE pathogenesis? Reverse transcription polymerase chain reaction (RT-PCR), polymerase chain reaction Q-PCR, and immunohistochemistry studies all suggest that ABCC6 is highly expressed in the liver and kidney [6, 25, 45]. Interestingly though, neither organ is, apparently, the primary site of pathology in PXE. No liver pathology has been described in PXE. Kidney defects are apparently more common, because 25% of PXE patients get calcification of arteries in kidneys, spleen, and pancreas revealed by echographic opacities, resulting in renovascular hypertension [12, 17, 47]. However, even within the kidney, the sites of ABCC6 expression, and PXE pathology, apparently, do not match.
RT-PCR and immunohistochemistry with anti-ABCC6 polyclonal antibodies suggest that ABCC6 is lowly expressed or absent at the main sites of PXE pathogenesis: skin, vessel wall, and RPE/Bruch’s membrane in the eye [6, 45]. The latter data strongly favor a systemic disease origin hypothesis [49], although a pathogenic systemic-local interaction cannot be excluded. In a few tissues, like lungs, both ABCC6 expression and PXE pathogenesis are absent [6, 25].
Abcc6 in mice: structure, function and physiological substrates
The mouse has been employed successfully as a model organism to study the function of several ABC transporters, such as ABCC1 [31, 52], ABCC3 [53], and ABCC7 (CFTR)[13]. The mouse genome contains homologues for at least 11 of the 13 human ABCC genes. Abcc6 is evolutionarily well conserved between mouse and man. The mouse Abcc6 is, with 1,498 amino acids, only four amino acids shorter than human ABCC6. The identity at the amino acid level is 78%. The predicted topology is similar to that of human ABCC6 with 17 transmembrane domains and two intracellular NBFs. In the mouse genome, Abcc6 and Abcc1 are physically separated, located, respectively, on chromosomes 7 and 16. The transport characteristics of mouse Abcc6 have not been studied yet. As Abcc6 knock out mice were recently generated, suitable tissues for transport studies are now available.
Targeted disruption of Abcc6 in the mouse: PXE-like signs
To clarify the function of Abcc6 and its relation with PXE, the Abcc6 gene was disrupted in the mouse by gene targeting. Two Abcc6 knock out mouse models (Abcc6 −/−) were generated [16, 24]. The strategies used for disrupting Abcc6 were quite similar and consisted of deleting the coding sequence of the first NBF. This should render any remaining gene product dysfunctional, as NBF regions are crucial for the transport function of ABC proteins. In addition, mutations in this region in man cause PXE (Fig. 1) [20, 27]. In both Abcc6 −/− mouse models, the production of Abcc6 protein is apparently abolished, as judged from the absence of Abcc6 immunoreactivity in the liver (Fig. 4) [16, 24].
The phenotype of the Abcc6 −/− mice was analyzed focusing on those tissues that are affected in PXE (skin, eye, and blood vessels). Necropsy of Abcc6 −/− mice revealed pathology specifically in all these tissues. Blood vessel pathology was most prominent in the mouse. In young Abcc6 −/− mice, calcification was observed in the wall of medium-sized arteries in the cortex of the kidney and in the capsule surrounding the sinuses of the vibrissae. It is currently not known why these vessel walls represent predilected sites of calcification in the Abcc6-deficient mouse. Calcification progresses with age and affects mice more than 12–15 months of age, also the aorta, coronary arteries, vena cava, as well as blood vessels in many of the tissues examined, such as muscle, tongue and adipose tissue. The calcium deposits are often found at or close to the elastic fibers in the vessel walls. In old Abcc6 −/− mice, also the eye and skin become involved, showing calcification in Bruch’s membrane of the eye and in the dermis. In conclusion, Abcc6 −/− mice spontaneously develop a PXE-like pathology, which confirms the crucial role of Abcc6 in the etiology of PXE.
Abcc6 and PXE in mice: expression, protein distribution, pathology
The phenotypic resemblance between PXE patients and Abcc6 −/− mice indicates that the Abcc6 −/− mouse is a useful tool to study the functional role of Abcc6 (as a transporter) in PXE pathophysiology. An important question in this respect is whether Abcc6 is present locally at the pathogenic sites. Several studies have examined the tissue distribution of Abcc6 mRNA and protein in the mouse. Significant levels of mRNA have been repeatedly found in liver, kidney and small intestine [33, 34, 36]. At the protein level, Abcc6 immunoreactivity is readily demonstrated at the basolateral membranes of hepatocytes and basal membranes of the proximal tubules in the kidney (Fig. 4) [16]. There are also reports of a more widespread distribution of messenger and protein in the mouse [3]. High sensitive RNAse protection assays [3] and RT-PCR [6, 34] have detected small amounts of Abcc6 transcripts in a variety of other tissues, including the sites of pathology. However, the biological significance of these low levels of mRNA remains questionable, especially because many of these messengers are Abcc6 splice variants harboring premature stopcodons [34]. At the protein level, a recent study using tissues from Abcc6 −/− mice as negative controls, failed to detect Abcc6 immunoreactivity at the pathogenic sites in skin, blood vessels and eye [16]. In summary, these expression studies did not support the local dysfunction of Abcc6 as the primary cause for PXE pathology. On the contrary, the data favor a systemic origin of PXE because the expression in liver, kidney, and small intestine put Abcc6 in a strategic position to control the blood values of its substrate. The nature of this substrate is currently not known. Analysis of the blood of Abcc6 −/− mice revealed no aberrant concentration of minerals, such as calcium. However, Abcc6 −/− mice do develop a reduction in plasma levels of high-density lipoprotein (HDL)-cholesterol, which suggests that Abcc6 may (also) be involved in lipid transport or metabolism.
Conclusions and perspectives
Five years ago, the discovery that PXE patients carry mutations in ABCC6 came as a surprise because a relation between this membrane transporter with PXE was not immediately apparent [6, 29]. Since then, this relation has been further strengthened, e.g., by the detection of ABCC6 mutations in up to 90% of the PXE patients and the PXE-like phenotype in Abcc6 knock out mice [16, 24]. Currently, ABCC6 is considered to be the only disease gene causing PXE.
Despite this increased certainty that ABCC6 mutations cause PXE, the function of ABCC6 and its role in PXE remain largely unresolved. Fortunately, Abcc6 knock out mice are now available and the close resemblance in phenotype with PXE patients suggest that they will be valuable for analysis of the role of Abcc6 in PXE.
Several questions need to be addressed. First, an important issue still is whether PXE is a systemic or local disease. This can be initially addressed by studying Abcc6 expression and localization of the protein in the mouse, with Abcc6 −/− tissues as negative controls. However, it cannot be completely excluded that low and hardly detectable levels of Abcc6 may have physiological relevance. Therefore, functional studies are required for a more definitive answer. These studies may consist of reintroducing Abcc6 in a tissue-specific manner in the Abcc6 −/− mouse.
The next urgent question is the identification of the substrate of ABCC6. Currently, hepatocytes are the most obvious cell type of choice for transport studies, because these cells express Abcc6 abundantly. Examination of the effect of Abcc6 deficiency on gene expression in the liver may suggest candidate substrates. In addition, suggestions for candidate substrates may come from analyzing the blood of PXE and normal persons. The first analysis of blood samples of the Abcc6 −/− mouse indicated that HDL-cholesterol values change in Abcc6 −/− mice [16]. However, no significant changes in HDL-cholesterol have been observed so far in our PXE patients (unpublished results).
In case of a local disease, fibroblasts are the cell type of choice for studies to identify the substrate specificity of ABCC6. Indications for the substrate may be obtained by comparing physiology and gene expression of cultured fibroblasts from PXE patients and from healthy control persons. Possibly, toxicity assays can be developed using toxic agents such as saltpeter fertilizers, which upon contact cause PXE-like skin lesions [10].
The final challenge will be to unravel PXE etiology and to prevent or even cure the disease. However, many aspects of PXE pathogenesis are still unknown. For example, in the eye of PXE patients, fundus signs, such as white punched out lesions, comet-like tails, and peau d’orange occur frequently. The histological and pathological correlate of these features is unknown. In tissues that develop a PXE-like pathology in the Abcc6 −/− mouse, the sequence of events can be analyzed in detail and we can try to intervene experimentally. In addition, the Abcc6 −/− mouse models will enable us to test a variety of potential experimental therapies for PXE, ranging from dietary intervention to gene therapy.
References
Bacchelli B, Quaglino D, Gheduzzi D, Taparelli F, Boraldi F, Trolli B, Le Saux O, Boyd CD, Ronchetti IP (1999) Identification of heterozygote carriers in families with a recessive form of pseudoxanthoma elasticum (PXE). Mod Pathol 12:1112–1123
Beck K, Hayashi K, Dang K, Hayashi M, Boyd CD (2005) Analysis of ABCC6 (MRP6) in normal human tissues. Histochem Cell Biol 123:517–528
Beck K, Hayashi K, Nishiguchi B, Le Saux O, Hayashi M, Boyd CD (2003) The distribution of Abcc6 in normal mouse tissues suggests multiple functions for this ABC transporter. J Histochem Cytochem 51:887–902
Belinsky MG, Chen ZS, Shchaveleva I, Zeng H, Kruh GD (2002) Characterization of the drug resistance and transport properties of multidrug resistance protein 6 (MRP6, ABCC6). Cancer Res 62:6172–6177
Bergen AA, Plomp AS, Gorgels TG, de Jong PT (2004) From gene to disease: pseudoxanthoma elasticum and the ABCC6 gene. Ned Tijdschr Geneeskd 148:1586–1589
Bergen AA, Plomp AS, Schuurman EJ, Terry S, Breuning M, Dauwerse H, Swart J, Kool M, van Soest S, Baas F, ten Brink JB, de Jong PT (2000) Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet 25:228–2231
Borst P, Elferink RO (2002) Mammalian ABC transporters in health and disease. Annu Rev Biochem 71:537–592
Cai L, Lumsden A, Guenther UP, Neldner SA, Zach S, Knoblauch H, Ramesar R, Hohl D, Callen DF, Neldner KH, Lindpaintner K, Richards RI, Struk B (2001) A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: implications for mutation analysis in pseudoxanthoma elasticum. J Mol Med 79:536–546
Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A (2005) Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations. J Med Genet 42:881–892
Christensen OB (1978) An exogenous variety of pseudoxanthoma elasticum in old farmers. Acta Derm Venereol 58:319–321
Connor PJJ, Edwards JE, Hollenhorst RW, Juergens JL, Perry HO (1961) Pseudoxanthoma elasticum and angioid streaks. A review of 106 cases. Am J Med 30:537–543
Crespi G, Derchi LE, Saffioti S (1992) Sonographic detection of renal changes in pseudoxanthoma elasticum. Urol Radiol 13:223–225
Dorin JR (1995) Development of mouse models for cystic fibrosis. J Inherit Metab Dis 18:495–500
Germain DP (2001) Pseudoxanthoma elasticum: evidence for the existence of a pseudogene highly homologous to the ABCC6 gene. J Med Genet 38:457–461
Goodman RM, Smith EW, Paton D, Bergman RA, Siegel CL, Ottesen OE, Shelley WM, Push AL (1963) Pseudoxanthoma elasticum: a clinical and histopathological study. Medicine (Baltimore) 42:297–334
Gorgels TG, Hu X, Scheffer GL, van der Wal AC, Toonstra J, de Jong PT, van Kuppevelt TH, Levelt CN, de Wolf A, Loves WJ, Scheper RJ, Peek R, Bergen AA (2005) Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum. Hum Mol Genet 14:1763–1773
Hodson EM, Antico VF, O’Neill P (1992) Hypertension associated with diffuse small artery calcification: a case report. Pediatr Nephrol 6:556–558
Hu X, Peek R, Plomp A, ten Brink J, Scheffer G, van Soest S, Leys A, de Jong PT, Bergen AA (2003) Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum. Invest Ophthalmol Vis Sci 44:1824–1829
Hu X, Plomp A, Gorgels T, Brink JT, Loves W, Mannens M, de Jong PT, Bergen AA (2004) Efficient molecular diagnostic strategy for ABCC6 in pseudoxanthoma elasticum. Genet Test 8:292–300
Hu X, Plomp A, Wijnholds J, ten Brink J, van Soest S, van den Born LI, Leys A, Peek R, de Jong PT, Bergen AA (2003) ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum. Eur J Hum Genet 11:215–224
Hu X, Plomp AS, van Soest S, Wijnholds J, de Jong PT, Bergen AA (2003) Pseudoxanthoma elasticum: a clinical, histopathological, and molecular update. Surv Ophthalmol 48:424–438
Ilias A, Urban Z, Seidl TL, Le Saux O, Sinko E, Boyd CD, Sarkadi B, Varadi A (2002) Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6). J Biol Chem 277:16860–16867
Katona E, Aslanidis C, Remenyik E, Csikos M, Karpati S, Paragh G, Schmitz G (2005) Identification of a novel deletion in the ABCC6 gene leading to Pseudoxanthoma elasticum. J Dermatol Sci 40:115–121
Klement JF, Matsuzaki Y, Jiang QJ, Terlizzi J, Choi HY, Fujimoto N, Li K, Pulkkinen L, Birk DE, Sundberg JP, Uitto J (2005) Targeted ablation of the abcc6 gene results in ectopic mineralization of connective tissues. Mol Cell Biol 25:8299–8310
Kool M, van der Linden M, de Haas M, Baas F, Borst P (1999) Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells. Cancer Res 59:175–182
Kornet L, Bergen AA, Hoeks AP, Cleutjens JP, Oostra RJ, Daemen MJ, van Soest S, Reneman RS (2004) In patients with pseudoxanthoma elasticum a thicker and more elastic carotid artery is associated with elastin fragmentation and proteoglycans accumulation. Ultrasound Med Biol 30:1041–1048
Le Saux O, Beck K, Sachsinger C, Silvestri C, Treiber C, Goring HH, Johnson EW, De Paepe A, Pope FM, Pasquali-Ronchetti I, Bercovitch L, Marais AS, Viljoen DL, Terry SF, Boyd CD (2001) A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum. Am J Hum Genet 69:749–764
Le Saux O, Urban Z, Goring HH, Csiszar K, Pope FM, Richards A, Pasquali-Ronchetti I, Terry S, Bercovitch L, Lebwohl MG, Breuning M, van den Berg P, Kornet L, Doggett N, Ott J, de Jong PT, Bergen AA, Boyd CD (1999) Pseudoxanthoma elasticum maps to an 820-kb region of the p13.1 region of chromosome 16. Genomics 62:1–10
Le Saux O, Urban Z, Tschuch C, Csiszar K, Bacchelli B, Quaglino D, Pasquali-Ronchetti I, Pope FM, Richards A, Terry S, Bercovitch L, De Paepe A, Boyd CD (2000) Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nat Genet 25:223–227
Lebwohl M, Neldner K, Pope FM, De Paepe A, Christiano AM, Boyd CD, Uitto J, McKusick VA (1994) Classification of pseudoxanthoma elasticum: report of a consensus conference. J Am Acad Dermatol 30:103–107
Lorico A, Rappa G, Finch RA, Yang D, Flavell RA, Sartorelli AC (1997) Disruption of the murine MRP (multidrug resistance protein) gene leads to increased sensitivity to etoposide (VP-16) and increased levels of glutathione. Cancer Res 57:5238–5242
Madon J, Hagenbuch B, Landmann L, Meier PJ, Stieger B (2000) Transport function and hepatocellular localization of mrp6 in rat liver. Mol Pharmacol 57:634–641
Maher JM, Slitt AL, Cherrington NJ, Cheng X, Klaassen CD (2005) Tissue distribution and hepatic and renal ontogeny of the multidrug resistance-associated protein (Mrp) family in mice. Drug Metab Dispos 33:947–955
Matzusaki Y, Nakano A, Jiang QJ, Pulkkinen L, Uitto J (2005) Tissue specific expression of the ABCC6 gene. J Invest Dermatol Nov 125(5):900–905
Miksch S, Lumsden A, Guenther UP, Foernzler D, Christen-Zach S, Daugherty C, Ramesar RK, Lebwohl M, Hohl D, Neldner KH, Lindpaintner K, Richards RI, Struk B (2005) Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6. Human Mutat 26:235–248
Mutch DM, Anderle P, Fiaux M, Mansourian R, Vidal K, Wahli W, Williamson G, Roberts MA (2004) Regional variations in ABC transporter expression along the mouse intestinal tract. Physiol Genomics 17:11–20
Neldner KH (1988) Pseudoxanthoma elasticum. Clin Dermatol 6:1–159
Pasquali R, I, Baccarani CM, Pincelli C, Bertazzoni GM (1986) Effect of selective enzymatic digestions on skin biopsies from pseudoxanthoma elasticum: an ultrastructural study. Arch Dermatol Res 278:386–392
Pasquali-Ronchetti I, Volpin D, Baccarani-Contri M, Castellani I, Peserico A (1981) Pseudoxanthoma elasticum. Biochemical and ultrastructural studies. Dermatologica 163:307–325
Passi A, Albertini R, Baccarani CM, de Luca G, De Paepe A, Pallavicini G, Pasquali R, I, Tiozzo R (1996) Proteoglycan alterations in skin fibroblast cultures from patients affected with pseudoxanthoma elasticum. Cell Biochem Funct 14:111–120
Plomp AS, Hu X, de Jong PT, Bergen AA (2004) Does autosomal dominant pseudoxanthoma elasticum exist? Am J Med Genet 126A:403–412
Pope FM (1975) Historical evidence for the genetic heterogeneity of pseudoxanthoma elasticum. Br J Dermatol 92:493–509
Quaglino D, Boraldi F, Barbieri D, Croce A, Tiozzo R, Pasquali R, I (2000) Abnormal phenotype of in vitro dermal fibroblasts from patients with pseudoxanthoma elasticum (PXE). Biochim Biophys Acta 1501:51–62
Ringpfeil F, Lebwohl MG, Christiano AM, Uitto J (2000) Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter. Proc Natl Acad Sci USA 97:6001–6006
Scheffer GL, Hu X, Pijnenborg AC, Wijnholds J, Bergen AA, Scheper RJ (2002) MRP6 (ABCC6) detection in normal human tissues and tumors. Lab Invest 82:515–518
Struk B, Neldner KH, Rao VS, St Jean P, Lindpaintner K (1997) Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1. Hum Mol Genet 6:1823–1828
Suarez MJ, Garcia JB, Orense M, Raimunde E, Lopez MV, Fernandez O (1991) Sonographic aspects of pseudoxanthoma elasticum. Pediatr Radiol 21:538–539
Trip MD, Smulders YM, Wegman JJ, Hu X, Boer JM, ten Brink JB, Zwinderman AH, Kastelein JJ, Feskens EJ, Bergen AA (2002) Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease. Circulation 106:773–775
Uitto J (2004) Pseudoxanthoma elasticum-a connective tissue disease or a metabolic disorder at the genome/environment interface? J Invest Dermatol 122:ix
van Soest S, Swart J, Tijmes N, Sandkuijl LA, Rommers J, Bergen AA (1997) A locus for autosomal recessive pseudoxanthoma elasticum, with penetrance of vascular symptoms in carriers, maps to chromosome 16p13.1. Genome Res 7:830–834
Walker ER, Frederickson RG, Mayes MD (1989) The mineralization of elastic fibers and alterations of extracellular matrix in pseudoxanthoma elasticum. Ultrastructure, immunocytochemistry, and X-ray analysis. Arch Dermatol 125:70–76
Wijnholds J, Evers R, van Leusden MR, Mol CA, Zaman GJ, Mayer U, Beijnen JH, van der Valk M, Krimpenfort P, Borst P (1997) Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein. Nat Med 3:1275–1279
Zelcer N, Wetering KV, Waart RD, Scheffer GL, Marschall HU, Wielinga PR, Kuil A, Kunne C, Smith A, Valk MV, Wijnholds J, Elferink RO, Borst P (2005) Mice lacking Mrp3 (Abcc3) have normal bile salt transport, but altered hepatic transport of endogenous glucuronides. J Hepatol Aug 1[epub ahead of print]
Acknowledgements
The authors wish to acknowledge the Stichting “Blindenpenning” Amsterdam and the “Algemene Nederlandse Vereniging ter Voorkoming van Blindheid (ANVVB)” for financial support. We thank Dr J. Toonstra for providing PXE skin tissue samples and Dr G. L. Scheffer for the help in clarifying the PXE tissue distribution.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bergen, A.A.B., Plomp, A.S., Hu, X. et al. ABCC6 and pseudoxanthoma elasticum. Pflugers Arch - Eur J Physiol 453, 685–691 (2007). https://doi.org/10.1007/s00424-005-0039-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-005-0039-0