Alternative titles; symbols
HGNC Approved Gene Symbol: ABCC6
SNOMEDCT: 252246005;
Cytogenetic location: 16p13.11 Genomic coordinates (GRCh38) : 16:16,149,565-16,223,494 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.11 | Arterial calcification, generalized, of infancy, 2 | 614473 | Autosomal recessive | 3 |
| Pseudoxanthoma elasticum | 264800 | Autosomal recessive | 3 | |
| Pseudoxanthoma elasticum, forme fruste | 177850 | Autosomal dominant | 3 |
ABCC6 belongs to the multidrug resistance-associated protein (MRP) subfamily of ATP-binding cassette (ABC) transmembrane transporters. MRPs are involved in drug resistance, particularly in association with cancer chemotherapy. Mutations in the ABCC6 gene cause pseudoxanthoma elasticum (PXE; see 264800), a heritable connective tissue disorder characterized by calcification of elastic fibers in skin, arteries, and retina (Bergen et al., 2000; Le Saux et al., 2000; Ringpfeil et al., 2000).
Multidrug resistance in cancer cells has been attributed to the overexpression of certain membrane proteins, several of which are members of the ATP-binding cassette (ABC) superfamily. Examples include MRP (158343) and MDR1 (171050). Longhurst et al. (1996) screened an E1000 leukemia cell cDNA library using an MRP probe. They cloned a novel cDNA encoding a 453-amino acid polypeptide that was similar to the C-terminal half of MRP. Whereas MRP contains 2 ABC domains and 12 transmembrane domains, the ARA protein contains 1 ABC domain and 5 transmembrane domains. Northern blot analysis showed that ARA was expressed as a 2.2-kb mRNA in an E1000 leukemia cell line, but not in the untransformed parental CEM cell line. Southern blot analysis revealed that, like MRP, the ARA gene was amplified in the genomic DNA of the E1000 cell line. The ABCC6 protein consists of 1,503 amino acids with a molecular mass of 165 kD, is located in the plasma membrane, and probably has 17 membrane-spanning helices grouped into 3 transmembrane domains (Le Saux et al., 2000). The 4.5-kb ABCC6 mRNA is expressed in several secretory tissues, but primarily in kidney and liver. By RT-PCR analysis using RNA isolated from tissues frequently affected by PXE, Bergen et al. (2000) detected expression of ABCC6 in retina, skin, and vascular tissue, although the highest level of expression was in the liver.
By Western blot analysis of transfected Chinese hamster ovary (CHO) cells, Belinsky et al. (2002) found that MRP6 migrated at the predicted molecular mass of about 152 kD and at 182 kD, which likely represents a glycosylated form.
Sinko et al. (2003) found that human ABCC6, when expressed by retroviral transduction in polarized mammalian cells (MDCKII), is exclusively localized to the basolateral membrane. In contrast to the in vitro translated protein, ABCC6 was glycosylated in MDCK cells. Limited proteolysis of the fully glycosylated and underglycosylated forms, followed by immunodetection with region-specific antibodies, indicated that asn15, located in the extracellular N-terminal region of ABCC6, is the only N-glycosylated site in the protein.
By in situ hybridization and immunohistochemical analysis, Beck et al. (2005) detected ABCC6 mRNA and protein in a wide range of epithelial cells of exocrine and endocrine tissues such as acinar cells in the pancreas, mucosal cells of the intestine, and follicular epithelial cells of the thyroid. Enteroendocrine G cells of the stomach showed strong immunostaining. In addition, ABCC6 mRNA and protein were present in most neurons of the brain, in alveolar macrophages in the lung, in lymph node lymphocytes, in hepatocytes, and in keratinocytes and epithelial cells of the ducts of sweat glands.
Using PCR, Matsuzaki et al. (2005) found that Abcc6 expression was highest in mouse liver and lower in kidney and small intestine. Second-round nested PCR revealed much weaker expression in brain, tongue, stomach, and eye. Subcloning and sequencing of distinct PCR products indicated that the 3-prime end is subject to aberrant splicing, resulting in each case in a premature termination codon. PCR analysis of cultured human cells revealed similar splice variations in the 3-prime end resulting in the skipping of exons 24 and 30 in epidermal keratinocytes, and exons 24, 26, and 28 in dermal fibroblasts. In fibroblasts, a minor PCR product represented alternative splicing of exon 7.
Kool et al. (1999) determined that the human ABCC6 gene contains 31 exons.
Ratajewski et al. (2008) found that the 5-prime upstream region of the ABCC6 gene contains a major Alu element of over 4.5 kb.
Belinsky and Kruh (1999) and Klein et al. (1999) suggested that ABCC6 function may be related to cellular detoxification rather than drug resistance. Bergen et al. (2000) commented that the molecules presumably transported by ABCC6 may be essential for extracellular matrix deposition or turnover of connective tissue at specific sites in the body. Given the high expression of ABCC6 in liver and kidney, ABCC6 substrates may be transported into the blood. A deficiency of specific ABCC6 substrates may affect a range of connective tissue sites throughout the body and specifically elastic fiber assembly.
By assaying membrane vesicles obtained from ABCC6-expressing insect cells, Ilias et al. (2002) found ABCC6 specifically bound MgATP and actively transported glutathione conjugates, including leukotriene-C4 and N-ethylmaleimide S-glutathione (NEM-GS), in an MgATP-dependent manner. 17-Beta-estradiol-17-beta-D-glucuronide was a weak transport substrate. The organic anions probenecid, benzbromarone, and indomethacin specifically inhibited ABCC6-mediated NEM-GS transport, and orthovanadate, a phosphotyrosine phosphatase inhibitor, completely inhibited NEM-GS transport.
Using similar substrates to those used by Ilias et al. (2002), Belinsky et al. (2002) found that MRP6 expressed in CHO cell membranes could transport glutathione conjugates but not glucuronate conjugates. Transfected cells also showed enhanced resistance to several anticancer agents. The highest levels of resistance were observed for the inhibitors of topoisomerase II (126430) etoposide and teniposide, followed by the anthracyclines doxorubicin and daunorubicin. MRP6-expressing CHO cells accumulated less etoposide compared with control transfected cells, indicating that MRP6 functions as a drug efflux pump.
Using a luciferase reporter gene construct, Jiang et al. (2006) examined the 2.6-kb human ABCC6 promoter. An NF-kappa-B (see NFKB1, 164011)-like sequence conferred strong expression in HepG2 hepatoma cells, but much weaker expression in cell lines of other tissue origin. Injection of the construct into mouse tail vein confirmed liver-specific expression. Testing of selected cytokines revealed that TGF-beta (190180) upregulated, while TNF-alpha (191160) and interferon-gamma (IFNG; 147570) downregulated, the promoter activity in HepG2 cells. The responsiveness to TGF-beta resided primarily within an SP1 (189906)/SP3 (601804) binding site. The expression of the ABCC6 promoter was markedly enhanced by SP1. Jiang et al. (2006) concluded that the expression of ABCC6 can be modulated by proinflammatory cytokines.
Using the ABCC6 promoter region in reporter gene assays in the HepG2 hepatoma cell line, Ratajewski et al. (2006) showed that all-trans retinoic acid caused significant induction of ABCC6 activity. They found 9-cis retinoic acid (9cRA), a specific RXR (see RXRA, 180245) receptor agonist, induced the ABCC6 promoter in a concentration-dependent manner. 9cRA also induced the expression of endogenous ABCC6 in HepG2 cells. The binding of RXR to the endogenous ABCC6 promoter was confirmed by chromatin immunoprecipitation experiments. Occupancy of the ABCC6 promoter by RXR was relatively high in unstimulated cells and increased further in 9cRA-treated cells.
Using the ABCC6 reporter construct described by Ratajewski et al. (2006) in a screen for ABCC6-regulating factors, Ratajewski et al. (2008) found that GATA3 (131320) repressed ABCC6 activity, and that SP1, PLAG1 (603026), and PLAGL1 (603044) induced ABCC6 activity. They identified 2 putative PLAG-binding sites on the reverse strand of the ABCC6 proximal promoter. Reporter gene assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation analysis showed that the more proximal site was bound and activated by PLAG1 and PLAGL1. Furthermore, overexpression of PLAG1 resulted in enhanced ABCC6 transcription in transfected human embryonic kidney cells.
Kuss et al. (1998) used fluorescence in situ hybridization to map the ARA gene to human chromosome 16p13.1. The gene order in this region is telomere--MYH11(160745)--MRP--ARA--centromere. The MRP and ARA genes are located within 9 kb of each other and are transcribed in opposite directions. Both MRP and ARA are deleted in a subgroup of inv(16) leukemias, and both are expressed in normal hematopoietic precursor cells.
Pseudogenes
Pulkkinen et al. (2001) identified 2 pseudogenes containing sequences highly homologous to the 5-prime end of the ABCC6 gene.
Pseudoxanthoma Elasticum
Simultaneously and independently, Bergen et al. (2000), Le Saux et al. (2000), and Ringpfeil et al. (2000) identified missense, nonsense, and splice site mutations as well as deletions and insertions in the ABCC6 gene causing pseudoxanthoma elasticum (PXE; 264800). Mutations appeared to represent autosomal recessive (Le Saux et al., 2000) and autosomal dominant (177850) (Bergen et al., 2000) modes of inheritance, and sporadic cases. By SSCP and heteroduplex analysis using genetic DNA from a cohort of 17 unrelated PXE patients, Le Saux et al. (2000) screened 109 exons within 5 PXE candidate genes in the chromosome 16p13.1 region for mutations. By screening the 31 exons of ABCC6 by SSCP, Le Saux et al. (2000) identified 6 mutations that were responsible for PXE in 10 of 17 patients. They identified a C-to-T substitution within exon 24 at nucleotide 3421, resulting in an arg-to-stop substitution at codon 1141 (R1141X; 603234.0001) in 6 unrelated families with autosomal recessive PXE. Bergen et al. (2000) identified mutations in ABCC6 causing autosomal dominant, autosomal recessive, and sporadic PXE. Bergen et al. (2000) found the R114X mutation in 2 families with autosomal dominant PXE. One patient had a large de novo deletion of chromosome 16 (603234.0010). Ringpfeil et al. (2000) reported a total of 8 pathogenetic mutations in the ABCC6 gene in 8 kindreds with PXE. They referred to the gene as MRP6 (multidrug resistance-associated protein-6). Examination of clinically unaffected family members in 4 multiplex families identified heterozygous carriers, consistent with an autosomal recessive inheritance pattern.
Le Saux et al. (2001) performed a mutation analysis of the ABCC6 gene in 122 unrelated patients with PXE, the largest cohort of patients studied to that time. They characterized 36 mutations, 28 of which were novel. Twenty-one were missense variants, 6 were small insertions or deletions, 5 were nonsense, 2 were alleles likely to result in aberrant mRNA splicing, and 2 were large deletions involving ABCC6. Although most mutations appeared to be unique variants, 2 disease-causing alleles occurred frequently in apparently unrelated individuals. Arg1141 to ter (R1141X; 603234.0001) was found in this patient cohort at a frequency of 18.8% and was preponderant in European patients. Deletion of nucleotides 23-29 (603234.0016) occurred at a frequency of 12.9% and was prevalent in patients from the United States. Putative disease-causing mutations were identified in approximately 64% of the 244 chromosomes studied, and 85.2% of the 122 patients were found to have at least 1 disease-causing allele. The results suggested that a fraction of the undetected mutant alleles could be either genomic rearrangements or mutations occurring in noncoding regions of the ABCC6 gene. A cluster of disease-causing variants was observed within exons encoding a large C-terminal cytoplasmic loop and in the C-terminal nucleotide-binding domain.
While implementing a strategy to screen for PXE by complete mutation analysis of the ABCC6 gene, Germain (2001) found evidence for the existence of at least 1 pseudogene highly homologous to the 5-prime end of ABCC6. Sequence variants in this ABCC6-like pseudogene could be mistaken for mutations in the ABCC6 gene and consequently lead to erroneous genotyping results in pedigrees affected with PXE.
Gernaub et al. (2001) identified a heterozygous missense mutation in exon 7 of the ABCC6 gene in a female PXE patient whose parents were second cousins. Despite complete scanning of the gene, no further mutation was evident. A heterozygous profile was also found in the proband's unaffected children. However, haplotype homozygosity was confirmed at chromosome 16p13.1, using both extragenic microsatellites and intragenic polymorphisms located 3-prime from the mutation, in agreement with the known consanguinity in the family. Taken together, the data indicated that PCR products of exon 7 of the ABCC6 gene were amplified from more than 2 genomic copies. This supported the existence of one or more ABCC6 pseudogenes highly homologous to the 5-prime end (exons 1-9) of the ABCC6 gene.
Pulkkinen et al. (2001) identified 2 pseudogenes containing sequences highly homologous to the 5-prime end of the ABCC6 gene. Nucleotide differences in flanking introns between these 2 pseudogenes and ABCC6 allowed them to design allele-specific primers that eliminated the amplification of both pseudogene sequences by PCR and provided reliable amplification of ABCC6-specific sequences only. The use of allele-specific PCR revealed 2 novel 5-prime-end PXE mutations.
In 59 unrelated Dutch patients with PXE, Hu et al. (2003) identified 17 different mutations, including 11 novel mutations, in the ABCC6 gene in 65 alleles. The R1141X mutation was by far the most common mutation, identified in 19 (32.2%) patients; the second most common mutation, which results in the deletion of exons 23-29 (603234.0016), was identified in 11 (18.6%) patients. In 20 patients, only 1 mutation in 1 allele was detected. Combined with previous mutation data, Hu et al. (2003) concluded that approximately 80% of the PXE mutations occur in the cytoplasmic domains of the predicted ABCC6 protein, especially the 2 nucleotide-binding fold (NBF) domains (NBF1 and NBF2) and the eighth cytoplasmic loop between the fifteenth and sixteenth transmembrane regions.
Hu et al. (2004) described an efficient molecular diagnostic strategy for ABCC6 in PXE. The 2 most frequent mutations, R1141X (603234.0001) and deletion of exons 23 through 29 (603234.0016), as well as a core set of mutations, were identified by restriction enzyme digestion and size separation on agarose gels. In the remaining patient group in which only 1 or no mutant allele was found, the complete coding sequence was analyzed using DHPLC. All variations found were confirmed by direct DNA sequencing. Finally, Southern blot was used to investigate the potential presence of small or large deletions. Twenty different mutations, including 2 novel mutations in the ABCC6 gene, were identified in 80.3% of the 76 patients, and 58.6% of the 152 ABCC6 alleles analyzed.
Chassaing et al. (2005) commented that mutations had been identified in PXE in most of the 31 ABCC6 exons and that no correlation between the nature or the location of the mutations and phenotype severity had been established.
Trip et al. (2002), Van Soest et al. (1997), and Bacchelli et al. (1999) emphasized the carriage of a sole ABCC6 mutation as a cardiovascular risk factor. Sherer et al. (2001) described limited phenotypic expression of PXE in parents of affected offspring.
Miksch et al. (2005) performed a mutation screen in ABCC6 using haplotype analysis in conjunction with direct sequencing to achieve a mutation detection rate of 97%. Their mutational analysis confirmed an earlier haplotype-based analysis and conclusions regarding a recessive-only mode of inheritance in PXE (Cai et al., 2000) through the identification of 2 mutated alleles in all individuals with PXE who appear in either consecutive or alternating generations of the same family. Their study demonstrated that the full phenotypic expression of the disorder requires 2 defective allelic copies of ABCC6 and that pseudodominance is the mode of transmission in presumed autosomal dominant families (i.e., the second parental disease allele 'marries into' the family). The apparent frequency of this mechanism was approximately 7.5% in their family cohort. Miksch et al. (2005) stated that in their families no heterozygote for a large deletion showed any apparent clinical sign of PXE according to category I diagnostic criteria.
Chassaing et al. (2005) provided a comprehensive catalog of ABCC6 mutations identified in PXE.
Pfendner et al. (2007) collected mutation data on an international case series of 270 patients with PXE (239 probands, 31 affected family members). In 134 patients with a known phenotype and both mutations identified, genotype-phenotype correlations were assessed. In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations clustered in exons 24 and 28, corresponding to the second nucleotide-binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X (603234.0001) and del23-29 (603234.0016) mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype-phenotype analysis failed to reveal a significant correlation between the type of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease.
Using multiplex ligation-dependent probe amplification (MLPA) to analyze 35 PXE patients with incomplete ABCC6 genotypes after exonic sequencing, Costrop et al. (2010) identified 6 multiexon deletions and 4 single-exon deletions and were thus able to characterized 25% of the unidentified disease alleles. The findings illustrated the instability of the ABCC6 genomic region and stressed the importance of screening for deletions in the molecular diagnosis of PXE.
Legrand et al. (2017) performed a molecular analysis on 458 French PXE probands clinically evaluated using the Phenodex score (PS). Complete molecular analysis of 306 cases allowed the identification of 538 mutational events (88% detection rate) with 142 distinct variants, of which 66 were novel. Missense variant distribution was specific to some regions and residues of ABCC6.
Generalized Arterial Calcification of Infancy 2
In a 28-year-old French man with PXE, who had a younger brother who died of generalized arterial calcification of infancy (GACI2; 614473) at age 15 months, Le Boulanger et al. (2010) identified compound heterozygosity for missense mutations in the ABCC6 gene (603234.0025 and 603234.0026), which were also found in heterozygosity in each of his unaffected parents, respectively. No disease-causing mutations were found in the known GACI1 (208000)-related gene, ENPP1 (173335). Although no DNA material was available from the deceased younger brother, his disease was presumed to be related to the familial ABCC6 mutations. Le Boulanger et al. (2010) concluded that GACI may represent an atypical and severe end of the vascular phenotypic spectrum of PXE.
Nitschke et al. (2012) analyzed the ABCC6 gene in 28 GACI patients from 25 unrelated families who were negative for mutation in the ENNP1 gene, as well as 2 unrelated GACI patients in whom only 1 ENNP1 mutation had been detected. They identified homozygosity or compound heterozygosity for mutations in ABCC6 in 8 unrelated GACI patients (see, e.g., 603234.0001, 603234.0002, 603234.0006, and 603234.0027-603234.0028). In 6 patients from 5 unrelated families, only 1 mutation was detected in ABCC6; the authors noted that there was no phenotypic difference between these patients and those with biallelic mutations in ABCC6, and stated that mutations in regulatory untranslated regions of ABCC6 might not have been detected by their approach. No mutation in the ABCC6 gene was found in 16 patients from 14 unrelated families, including the 2 patients who were known to carry monoallelic mutations in ENNP1. Overall, 13 different ABCC6 mutations were identified in GACI patients, all but 2 of which had been previously identified in typical PXE patients who had a much milder phenotype than the GACI patients. Based on the considerable overlap of phenotype and genotype of GACI and pseudoxanthoma elasticum, Nitschke et al. (2012) suggested that GACI and PXE represent 2 ends of a clinical spectrum of ectopic calcification and other organ pathologies rather than 2 distinct disorders.
The Afrikaner population of South Africa is of Dutch, German, and French Huguenot descent and has its origin in the first European immigrant settlements at the Cape of Good Hope during the 17th century. Torrington and Viljoen (1991) proposed that the basis for the high prevalence of PXE in the Afrikaner population is a founder effect. An initial genealogic study traced the ancestry of 20 Afrikaner families with PXE back to potentially only 4 individuals, suggesting that this disorder is most likely derived from these original founders in South Africa. To study this possibility further, Le Saux et al. (2002) performed haplotype and mutation analyses in 17 of the 20 originally analyzed Afrikaner families, and identified 3 common haplotypes and 6 different disease-causing variants. Three of these mutant alleles were missense variants, 2 were nonsense mutations, and 1 was a single-basepair insertion. The most common variant, arg1339 to cys (R1339C; 603234.0017), accounted for 53% of the PXE alleles, whereas other mutant alleles appeared at lower frequencies ranging from 3 to 12%. Haplotype analysis of the Afrikaner families showed that the 3 most frequent mutations were identical by descent, indicating a founder origin of PXE in this population.
Chassaing et al. (2005) suggested that the proposed prevalence of PXE of 1 in 25,000 may be an underestimation. Consequently, the prevalence of heterozygous carriers and the prevalence of different organ involvement in carriers of 1 or 2 ABCC6 mutations are not precisely known.
Since the ABCC6 gene is expressed primarily, if not exclusively, in the liver and kidneys, Ringpfeil et al. (2001) suggested that PXE is a primary metabolic disorder with secondary involvement of elastic fibers, a situation comparable to the secondary involvement of connective tissue elements in homocystinuria (236200) and alkaptonuria (203500).
ABCC6 is a member of the large ATP-dependent transmembrane transporter family. Chassaing et al. (2005) commented that the association of PXE to ABCC6 efflux transport alterations raised a number of pathophysiology hypotheses, among them, the idea that PXE is a systemic metabolic disease resulting from lack or accumulation over time in the bloodstream of molecules interacting with the synthesis, turnover, and/or maintenance of extracellular matrix (ECM).
Since ABCC6 is expressed primarily in the liver, Jiang and Uitto (2006) likewise supported the notion that PXE is a metabolic disease.
In an investigation of the functional relationship between ABCC6 deficiency and elastic fiber calcification, Le Saux et al. (2006) speculated that ABCC6 deficiency in PXE patients induces a persistent imbalance in circulating metabolite(s) which impairs the synthetic abilities of normal elastoblasts or specifically alters elastic fiber assembly. They found that PXE fibroblasts cultured with normal human serum expressed and deposited increased amounts of proteins, but structurally normal elastic fibers. Normal and PXE fibroblasts as well as normal smooth muscle cells deposited abnormal aggregates of elastic fibers when maintained in the presence of serum from PXE patients. The expression of tropoelastin (see 130160) and other elastic fiber-associated genes was not significantly modulated by the presence of PXE serum. These results indicated that certain metabolites present in PXE sera interfered with the normal assembly of elastic fibers in vitro and suggested that PXE is a primary metabolic disorder with secondary connective tissue manifestations.
To elucidate the pathogenesis of PXE, Klement et al. (2005) generated a transgenic mouse by targeted ablation of the mouse Abcc6 gene. Abcc6-null mice were negative for expression of Mrp6 in the liver, and necropsies revealed profound mineralization of several tissues including skin, arterial blood vessels, and retina, while heterozygous animals were indistinguishable from the wildtype mice. Particularly striking was the mineralization of vibrissae, as confirmed by von Kossa and alizarin red stains. Electron microscopy revealed mineralization affecting both elastic structures and collagen fibers. Mineralization of vibrissae was noted as early as 5 weeks of age and was progressive with age in Abcc6 -/- mice but was not observed in heterozygous or wildtype mice up to 2 years of age. Total body computerized tomography scan of Abcc6 -/- mice showed mineralization in skin and subcutaneous tissue as well as in kidneys. These data demonstrated aberrant mineralization of soft tissues in PXE-affected organs, and consequently, these mice recapitulated features of this complex disease.
Gorgels et al. (2005) generated Abcc6 -/- mice and showed by light and electron microscopy that Abcc6 -/- mice spontaneously developed calcification of elastic fibers in blood vessel walls and in Bruch membrane in the eye. No clear abnormalities were seen in the dermal extracellular matrix. Calcification of blood vessels was most prominent in small arteries in the cortex of the kidney, but in old mice, it occurred also in other organs and in the aorta and vena cava. Monoclonal antibodies against mouse Abcc6 localized the protein to the basolateral membranes of hepatocytes and the basal membrane in renal proximal tubules, but failed to show the protein at the pathogenic sites. Abcc6 -/- mice developed a 25% reduction in plasma HDL cholesterol and an increase in plasma creatinine levels, which may be due to impaired kidney function. No changes in serum mineral balance were found. Gorgels et al. (2005) concluded that the phenotype of the Abcc6 -/- mouse shares calcification of elastic fibers with human PXE pathology, and supports the hypothesis that PXE is a systemic disease.
To characterize the mineralization process in PXE, Jiang et al. (2007) examined a PXE animal model, the Abcc6 -/- mouse, with respect to specific proteins serving as inhibitors of mineralization. The levels of calcium and phosphate in serum of these mice were normal, but the Abcc6 -/- serum had less ability to prevent the mineral deposition induced by inorganic phosphate in a cell culture system. Addition of fetuin-A (138680) to the culture system prevented the mineralization. The calcium-phosphate product was markedly elevated in the mineralized vibrissae of Abcc6 -/- mice, an early biomarker of the mineralization process, consistent with histopathologic findings. Levels of fetuin-A were slightly decreased in Abcc6 -/- serum, and positive immunostaining for matrix-Gla-protein (MGP; 154870), fetuin-A, and ankylosis protein (ANK; 605145) as well as alkaline phosphatase activity were strongly associated with the mineralization process. In situ hybridization demonstrated that the genes for MGP and Ank were expressed locally in vibrissae, whereas fetuin-A was expressed highly in the liver. These data suggested that the deposition of the bone-associated proteins spatially coincides with mineralization and actively regulates this process locally and systemically.
In the Dyscalc1 mouse model of dystrophic cardiac calcification (DCC), Meng et al. (2007) studied 2 intercrosses and identified Abcc6 as the causative gene, which was confirmed by transgenic complementation. The authors noted that myocardial calcification has not been reported as a phenotype associated with human PXE or mouse Abcc6-knockout models.
In all mouse strains positive for DCC, Aherrahrou et al. (2008) identified a missense mutation at the 3-prime border of exon 14 of the Abcc6 gene that created an additional donor splice site. The alternative transcript lacked the last 5 nucleotides of exon 14, resulting in premature termination at codon 684, and leading to Abcc6 protein deficiency in DCC-susceptible mice.
Jiang et al. (2009) found that grafting of wildtype mouse muzzle skin onto the back of Abcc6-knockout mice resulted in abnormal mineralization of vibrissae consistent with PXE, whereas grafting of Abcc6-knockout mouse muzzle skin onto wildtype mice did not. The data implied that PXE does not result from localized defect based on resident cellular abnormalities but from a change of metabolite(s) in serum. These findings implicate circulatory factors as a critical component of the mineralization process and supported the notion that PXE is a secondary mineralization of connective tissues. In addition, the findings suggested that the abnormal mineralization process could possibly be countered or even reversed by changes in the homeostatic milieu.
Pseudoxanthoma Elasticum
In a large consanguineous Italian family segregating autosomal recessive pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2000) identified a C-to-T transition at nucleotide 3421 in exon 24 of the ABCC6 gene, resulting in an arg-to-ter substitution at codon 1141 (R1141X). All unaffected individuals but 1 were heterozygous carriers; affected individuals were homozygous for this mutation. This variant was not found in the control panel of 200 normal alleles and cosegregated in homozygous or compound heterozygous state with the PXE phenotype in families. This mutation was also identified in 5 unrelated pedigrees. R1141X was found in homozygous state in unrelated patients with autosomal recessive PXE from the United Kingdom and Belgium. Haplotype analysis of the PXE locus in families with the R1141X mutation revealed that this mutation was segregating with different haplotypes, suggesting that R1141X may be a recurrent mutation in ABCC6. Testing of cultured skin fibroblasts showed no ABCC6 mRNA in patients carrying the R1141X mutation from the large Italian pedigree.
Bergen et al. (2000) identified this mutation in 2 families segregating autosomal dominant PXE (177850).
In a family in which 2 brothers and a sister had PXE, Ringpfeil et al. (2000) demonstrated that the affected individuals were compound heterozygotes for the R1141X mutation and an R1268Q mutation (603234.0011).
In a cohort of 101 unrelated patients with PXE, Le Saux et al. (2001) found that the R1141X mutant allele was present in 28.4% of European alleles and only 4.1% of U.S. alleles. Also, this nonsense mutation was unequally distributed among European countries. The frequency of homozygotes was in Hardy-Weinberg equilibrium in the European population.
Hu et al. (2003) demonstrated a founder effect for the R1141X mutation in the Netherlands. They identified the mutation in 19 alleles in 16 Dutch patients with PXE, in heterozygous, homozygous, or compound heterozygous form. Expression of the normal allele in heterozygotes was predominant; no or very low expression was found in homozygotes. The mutation induced instability of the aberrant mRNA. Hu et al. (2003) suggested that the PXE phenotype of the R1141X mutation most likely results from complete loss of function or functional haploinsufficiency of ABCC6.
In the study of Trip et al. (2002), the presence of a single R1141X mutation in ABCC6 appeared to be an independent risk factor for coronary heart disease in young people.
Generalized Arterial Calcification of Infancy 2
In 2 patients with generalized arterial calcification of infancy-2 (GACI2; 614473), Nitschke et al. (2012) identified compound heterozygosity for 2 mutations in the ABCC6 gene. A French female infant with GACI who died at 6 weeks of age, who had calcification of the coronary arteries and other arteries, severe hypertension, and heart failure, was compound heterozygous for R1141X and R1314W (603234.0006). A 3-year-old Spanish boy with GACI who had calcification of the splenic and pancreatic arteries, nephrocalcinosis, severe hypertension, cardiomegaly, psychomotor retardation, and abdominal distention, was compound heterozygous for R1141X and R518X (603234.0027).
Pseudoxanthoma Elasticum, Forme Fruste, Digenic, ABCC6/GGCX
In a woman and her sister with biopsy-confirmed PXE, Li et al. (2009) identified compound heterozygosity for the R1141X mutation and a mutation in the GGCX gene (V255M; 137167.0012). Neither had evidence of a coagulopathy and the skin phenotype was mild (see 177850), but skin biopsies showed undercarboxylated matrix gla proteins (MGP; 154870) in the areas of abnormal mineralization. Since R1141X in the heterozygous state is usually not associated with clinical features, the findings suggested that the women had digenic inheritance of PXE. In contrast, 2 other family members who were compound heterozygous for R1141X and another mutation in the GGCX gene (S300F; 137167.0013) had no signs of either disorder on clinical exam but refused further clinical testing. Plasma levels of undercarboxylated total MGP of the 2 clinically unaffected individuals were at the lower end of normal. Although the reasons for the lack of clinical findings in the 2 unaffected family members remained unclear, Li et al. (2009) concluded that undercarboxylation of MGP plays a critical role in aberrant mineralization of tissues in PXE.
Pseudoxanthoma Elasticum
In patients with autosomal recessive pseudoxanthoma elasticum (PXE; 264800) from 2 families, Le Saux et al. (2000) found that affected individuals carried a G-to-T transversion at the +1 position of intron 21 of the ABCC6 gene, affecting the donor splice site. One of the families was from the United Kingdom, and the other was from the United States. The family from the U.K. carried the R1141X mutation (603234.0001) on the other allele; in the American family, the other mutation was R1138Q (603234.0003).
Generalized Arterial Calcification of Infancy 2
In a Canadian female infant with generalized arterial calcification of infancy (GACI2; 614473), originally reported by Glatz et al. (2006), who died at 6.5 weeks of age of myocardial infarction with calcification of the aorta and coronary, pulmonary, and renal arteries and occlusion of the right coronary artery, Nitschke et al. (2012) identified compound heterozygosity for 2 splice site mutations in the ABCC6 gene, a G-T transversion in intron 21 (IVS21+1G-T) and an IVS26-1G-A (603234.0015), both predicted to cause a frameshift resulting in a premature termination codon.
In a family with autosomal recessive pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2000) identified a G-to-A transition at nucleotide 3413 of the ABCC6 gene, resulting in an arginine-to-glutamine substitution at codon 1138 (R1138Q). This mutation was found in compound heterozygosity with the IVS21+1G-T mutation (603234.0002).
In a so-called sporadic case of PXE, Ringpfeil et al. (2000) identified an R1138Q mutation in the ABCC6 gene in compound heterozygosity with the R1268 mutation (603234.0011). Arginine-1138 is the same codon as that affected in the R1138W mutation (603234.0012); in the latter mutation, the nucleotide change is 3412C-T.
In a family with autosomal recessive pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2000) found affected individuals to be homozygous for a G-to-C transversion at nucleotide 3341 of the ABCC6 gene, resulting in an arg-to-pro substitution at codon 1114 (R1114P) in exon 24. This mutation was found in homozygosity.
In a patient thought to represent an isolated case of autosomal dominant pseudoxanthoma elasticum (177850), Le Saux et al. (2000) found a deletion of a T at nucleotide 3775 of the ABCC6 gene. This was a de novo mutation in the patient, and no mutations were found in the other allele of ABCC6 by screening using SSCP.
Plomp et al. (2009) examined a group of 15 adults homozygous for the 3775delT mutation and 44 individuals heterozygous for this mutation from a genetically isolated population in the Netherlands. All participants filled out a questionnaire and underwent standardized dermatologic and ophthalmologic examinations with photography of skin and fundus abnormalities. Skin biopsies from affected skin or a predilection site and/or a scar were examined and compared with biopsies from controls. Plomp et al. (2009) found that skin abnormalities, ophthalmologic signs, and cardiovascular problems varied greatly among the 15 homozygous participants. There was no correlation among severity of skin, eyes, or cardiovascular abnormalities. None of the 44 heterozygous participants had any sign of pseudoxanthoma elasticum on dermatologic, histopathologic, and/or ophthalmologic examination, but 32% had cardiovascular disease.
Pseudoxanthoma Elasticum
In a patient with autosomal recessive pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2000) identified a C-to-T transition at nucleotide 3940 of the ABCC6 gene, resulting in an arg-to-trp substitution at codon 1314 (R1314W). This mutation was found in homozygosity in one family.
Generalized Arterial Calcification of Infancy 2
In a 5-year-old boy with generalized arterial calcification of infancy (GACI2; 614473), Nitschke et al. (2012) identified homozygosity for the R1314W mutation. The boy was born as the first of dizygotic twins, and his twin brother was unaffected. The patient had calcification of the aorta and pulmonary, coronary, and renal arteries as well as other arteries, and stippled calcifications of proximal epiphyses of humeri, femora, pelvic cartilage, larynx, and mandible. He had severely decreased biventricular systolic function, marked cardiomegaly, and severe mitral insufficiency, as well as hypertension and respiratory insufficiency. Cerebral MRI revealed diffuse white matter disease, with cystic encephalomalacia, and laboratory analysis showed hyperbilirubinemia, anemia, and thrombocytopenia. Nitschke et al. (2012) also identified the R1314W mutation in compound heterozygosity in 2 unrelated GACI patients, a French female infant who died at 6 weeks of age and also carried an R1141X mutation (603234.0001), and an Afro-Caribbean male infant who died at 8 weeks of age with generalized arterial stenosis, myocardial infarction, and hypertension and also carried a 1-bp insertion (450insC; 603234.0028) in exon 4 of the ABCC6 gene, predicted to result in a premature stop codon and a truncated protein. In addition, in a 3-year-old South African girl with GACI, Nitschke et al. (2012) identified only a heterozygous R1314W mutation, but noted that mutations in regulatory untranslated regions of ABCC6 might not have been detected by their technique. In the South African child, onset of symptoms occurred at 2.5 years of age, and included calcification of the aorta, spleen, and pancreas, nephrocalcinosis, failure to thrive, hypertension, and heart failure.
In a large autosomal recessive pseudoxanthoma elasticum (PXE; 264800) family, Bergen et al. (2000) identified the deletion of a T at nucleotide 3798 of the ABCC gene in homozygosity. This mutation results in a frameshift and premature chain termination.
In 2 families segregating what was thought to be autosomal dominant pseudoxanthoma elasticum (177850), Bergen et al. (2000) identified a 4-bp insertion, AGAA, at nucleotide 4243 in exon 30. This insertion causes a frameshift resulting in the disruption of the Walker B motif and a protein longer by 24 amino acids.
In a patient with pseudoxanthoma elasticum (177850), Bergen et al. (2000) identified a 22-basepair deletion from nucleotides 1967 through 1989 of the ABCC6 gene in heterozygosity. The other allele appeared to be wildtype.
In a patient with pseudoxanthoma elasticum (177850), Bergen et al. (2000) detected a large deletion encompassing the ABCC6 gene as well as the MYH11 (160745) and ABCC1 (158343) genes. The other allele appeared to be wildtype.
Ringpfeil et al. (2000) found an arg1268-to-gln (R1268Q) mutation in compound heterozygous state in 3 presumably unrelated families with pseudoxanthoma elasticum (PXE; 264800). In 2 families, the mutation was combined with R1141X (603234.0001); in 1 family, it was combined with R1138Q (603234.0003).
In one of the families with PXE in which the R1141X mutation had been identified by Ringpfeil et al. (2000), Germain et al. (2000) identified a 3803G-A transition in exon 27 of the ABCC6 cDNA, resulting in an R1268Q mutation. To their surprise, the R1268Q variant was found in homozygous state in the proband's unaffected husband. They investigated the R1268Q mutation and found the Q1268 allele at a relatively high frequency (0.19) in a control population of 62 Caucasians. Genotype frequencies were in Hardy-Weinberg equilibrium, and 3 healthy volunteers were homozygous for the Q1268 allele. R1268Q is thus a harmless polymorphism when present in homozygous state.
In a familial case of pseudoxanthoma elasticum (PXE; 264800), Ringpfeil et al. (2000) found homozygosity for an arg1138-to-trp (R1138W) mutation in the ABCC6 gene due to a 3412C-T transition. The mutation was found in homozygous state in the proband's mother and in heterozygous state in her father, creating a pedigree pattern of pseudodominance. The same codon is involved in the R1138Q mutation due to a 3413G-A transition (603234.0003). Ringpfeil et al. (2001) discussed the same pedigree, derived from a consanguineous French Canadian PXE family.
Ringpfeil et al. (2001) studied the ABCC6 mutation in 4 multiplex families with pseudoxanthoma elasticum (PXE; 264800) inherited in an autosomal recessive pattern. In each family, the proband was a compound heterozygote for a single-bp substitution mutation and a deletion of approximately 16.5 kb spanning the site of the single-bp substitution in trans (i.e., on the homologous chromosome 16) (603234.0016). In 2 of the families the single-nucleotide substitution was 3490C-T (R1164X); in 1, it was R1141X (603234.0001); and in another, it was a splice site mutation, 3736-1G-A (603234.0015). In all 4 families the patients were first thought to be homozygous for the nondeletion mutation. The deletion mutation was shown to extend from intron 22 to intron 29, resulting in out-of-frame deletion of 1,213 nucleotides from the corresponding mRNA and causing elimination of 505 amino acids from the MRP6 polypeptide. The deletion breakpoints were precisely the same in all 4 families, which were of different ethnic backgrounds, and haplotype analysis by 13 microsatellite markers suggested that the deletion had occurred independently. Deletion breakpoints within introns 22 and 29 were embedded within AluSx repeat sequences, specifically in a 16-bp segment of DNA, suggesting Alu-mediated homologous recombination as a mechanism.
For discussion of the 1,213-bp deletion in the ABCC6 gene that was found in compound heterozygous state in patients with pseudoxanthoma elasticum (PXE; 264800) by Ringpfeil et al. (2001), see 603234.0013.
For discussion of the splice site mutation (IVS26-1G-A) in the ABCC6 gene that was found in compound heterozygous state in patients with pseudoxanthoma elasticum (PXE; 264800) by Ringpfeil et al. (2001), see 603234.0013.
For discussion of the IVS26-1G-A mutation in the ABCC6 gene that was found in compound heterozygous state in a patient with generalized arterial calcification of infancy-2 (GACI2; 614473) by Nitschke et al. (2012), see 603234.0002.
In a cohort of 101 unrelated patients with pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2001) identified a 16.4-kb deletion of the ABCC6 gene (deletion of exons 23-29) in 12.9% of mutant alleles. The frequency was very different in Europe and the United States, being 4.3% and 28.4%, respectively. The frequency of individuals homozygous for this mutation was observed to be in Hardy-Weinberg equilibrium in the United States.
In 17 Afrikaner families in South Africa with autosomal recessive pseudoxanthoma elasticum (PXE; 264800), Le Saux et al. (2002) found that 53% of the PXE-associated alleles of the ABCC6 gene had a 4015C-T transition, which caused an arg1339-to-cys (R1339C) mutation. Haplotype analysis showed that the mutation was identical by descent in these families.
In a family in which PXE classified as 'definite' occurred in 2 generations, Plomp et al. (2004) detected an arg1459-to-cys substitution (R1459C) in the ABCC protein on 1 allele only. The authors considered the diagnosis of PXE definite if 2 of the following 3 criteria were present: yellowish papules and/or plaques on the lateral side of the neck and/or flexural areas of the body; typical histopathological changes in a skin biopsy after von Kossa staining; and the presence of peau d'orange, angioid streaks, or comet-like streaks in the retina. The mother of this family and one of her sons fulfilled all 3 criteria. Plomp et al. (2004) stated that the R1459C mutation might be one that could cause PXE in the heterozygous state (177850). In their review of families with putative autosomal dominant PXE, including this family and 2 others examined by them, the authors noted that they did not find a single family with definite PXE in 3 or more generations.
Bergen (2006) stated that the family with the apparently heterozygous R1459C mutation studied by Plomp et al. (2004) remained 'an interesting puzzle and is perhaps the always existing 'exception to the rule'.'
In a cohort of 122 unrelated patients with pseudoxanthoma elasticum (PXE; 264800) from several countries, Le Saux et al. (2001) found a 3892G-T transversion in exon 28 of the ABCC6 gene that resulted in a val1298-to-phe (V1298F) substitution. The mutation was present in heterozygosity in 2 alleles from patients from the United States, for an allele frequency among 74 United States alleles of 2.7%. The mutation was not found in the European population.
Ilias et al. (2002) showed that the V1298F mutation, localized to the C-terminal cytoplasmic domain of ABCC6, did not affect the expression of the ABCC6 protein in infected insect cells, but that the protein was essentially inactive in the MgATP-dependent transport of N-ethylmaleimide S-glutathione (NEM-GS) or leukotriene-C4.
In a cohort of 122 unrelated patients with pseudoxanthoma elasticum (PXE; 264800) from several countries, Le Saux et al. (2001) found a 3904G-A transition in exon 28 of the ABCC6 gene that resulted in a gly1302-to-arg (G1302R) amino acid substitution in the second intracellular nucleotide-binding domain. The mutation, present in homozygosity, occurred in a total of 4 alleles from patients from the United States, giving an allele frequency of 5.4% in a total of 74 United States alleles. It was not found in the European population.
Ilias et al. (2002) showed that the G1302R mutation did not affect the expression of the ABCC6 protein in infected insect cells, but that the protein was essentially inactive in the MgATP-dependent transport of N-ethylmaleimide S-glutathione (NEM-GS) or leukotriene-C4.
In a cohort of 122 unrelated patients with pseudoxanthoma elasticum (PXE; 264800) from several countries, Le Saux et al. (2001) found a 3961G-A transition in exon 28 of the ABCC6 gene that resulted in a gly1321-to-ser (G1321S) substitution in the second intracellular nucleotide-binding domain. They found the mutation in heterozygosity in 1 of 74 United States alleles, for an allele frequency of 1.4%. It was not found in the European population.
Ilias et al. (2002) showed that the G1321S mutation did not affect the expression of the ABCC6 protein in infected insect cells, but that the protein was essentially inactive in the MgATP-dependent transport of N-ethylmaleimide S-glutathione (NEM-GS) or leukotriene-C4.
Chassaing et al. (2004) described a pedigree of pseudoxanthoma elasticum (PXE; 264800) with pseudodominant inheritance. Two affected sibs carried 3 distinct mutations of the ABCC6 gene. The brother carried a 3712G-C transversion in exon 26 that resulted in an asp1238-to-his substitution (D1238H), and a 3389C-T transition in exon 24 that resulted in a thr1130-to-met substitution (T1130M; 603234.0024). His sister carried the T1130M mutation and a 33-bp deletion (603234.0023). The mother, who had PXE also, was deduced to a compound heterozygote for the deletion and T1130M, whereas the father was assumed to be heterozygous for the D1238H mutation which was shared by the sibs; however, DNA was not available for study on either parent.
In the Algerian pedigree studied by Chassaing et al. (2004), a female patient with pseudoxanthoma elasticum (PXE; 264800) carried a 33-bp deletion in exon 9 of the ABCC6 gene (1088-1120del) in compound heterozygosity with a missense mutation (T1130M; 603234.0024). The mutation led to the deletion of 11 amino acids in the transmembrane and intracellular domains (Gln363_Arg373del).
In the Algerian pedigree studied by Chassaing et al. (2004), a woman with pseudoxanthoma elasticum (PXE; 264800) carried a 33-bp deletion in exon 9 of the ABCC6 gene (603234.0022) in compound heterozygosity with a 3389C-T transition in exon 24, resulting in a thr1130-to-met (T1130M) substitution. Her brother was compound heterozygous for T1130M and an asp1230-to-his (D1238H) substitution.
In a 28-year-old French man with pseudoxanthoma elasticum (PXE; 264800), who had a younger brother who died of generalized arterial calcification of infancy (GACI2; 614473) at age 15 months, Le Boulanger et al. (2010) identified compound heterozygosity for missense mutations in the ABCC6 gene: an arg765-to-gln (R765Q) substitution and a gln1406-to-lys (Q1406K; 603234.0026) substitution. The mutations were found in heterozygosity in each of his unaffected parents, respectively. Although no DNA material was available from the deceased younger brother, his disease was presumed to be related to the familial ABCC6 mutations. Le Boulanger et al. (2010) concluded that GACI may represent an atypical and severe end of the vascular phenotype spectrum of PXE. (The mutations identified by Le Boulanger et al. (2010) were listed as R765Q and Q1406K in their text, but as E765Q and E1406K in their Figure 3.)
The R765Q mutation in exon 18 of the ABCC6 gene has also been identified in heterozygosity and in compound heterozygosity with another ABCC6 mutation in patients with PXE (see Le Saux et al., 2001 and Miksch et al., 2005, respectively).
For discussion of the gln1406-to-lys (Q1406K) mutation in the ABCC6 gene that was identified in compound heterozygous state in a man with pseudoxanthoma elasticum (PXE; 264800) and in his brother with generalized arterial calcification of infancy-2 (GACI2; 614473) by Le Boulanger et al. (2010), see 603234.0025.
Generalized Arterial Calcification of Infancy 2
In a 3-year-old Spanish boy with generalized arterial calcification of infancy (GACI2; 614473), who had calcification of the splenic and pancreatic arteries, nephrocalcinosis, severe hypertension, cardiomegaly, psychomotor retardation, and abdominal distention, Nitschke et al. (2012) identified compound heterozygosity for 2 mutations in the ABCC6 gene: an R1141X substitution (603234.0001) and a 1552C-T transition in exon 12, resulting in an arg518-to-ter (R518X) substitution.
Pseudoxanthoma Elasticum
The R518X mutation has been identified in compound heterozygosity with another ABCC6 mutation in patients with pseudoxanthoma elasticum (PXE; 264800) (see, e.g., Meloni et al., 2001 and Miksch et al., 2005).
For discussion of the 1-bp insertion (450insC) in the ABCC6 gene that was found in compound heterozygous state in patients with generalized arterial calcification of infancy-2 (GACI2; 603234) by Nitschke et al. (2012), see 603234.0006.
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