Development of a Rapid, Reliable Genetic Test for Pseudoxanthoma Elasticum
2007; Elsevier BV; Volume: 9; Issue: 1 Linguagem: Inglês
10.2353/jmoldx.2007.060093
ISSN1943-7811
AutoresYanggu Shi, Sharon F. Terry, Patrick F. Terry, Lionel Bercovitch, Gary F. Gerard,
Tópico(s)Genetic factors in colorectal cancer
ResumoMutations in the human ABCC6 gene cause pseudoxanthoma elasticum (PXE), a hereditary disorder that impacts the skin, eyes, and cardiovascular system. Currently, the diagnosis of PXE is based on physical findings and histological examination of a biopsy of affected skin. We have combined two simple, polymerase chain reaction (PCR)-based methods to develop a rapid, reliable genetic assay for the majority of known PXE mutations. After PCR amplification and heteroduplex formation, mutations in exon 24 and exon 28 of the ABCC6 gene were detected with Surveyor nuclease, which cleaves double-stranded DNA at any mismatch site. Mutations originating from deletion of a segment of the ABCC6 gene between exon 23 and exon 29 (ex23_ex29del) were detected by long-range PCR. Size analysis of digestion fragments and long-range PCR products was performed by agarose gel electrophoresis. The methods accurately identified mutations or the absence thereof in 16 affected individuals as confirmed by DNA sequencing. Fifteen patients had one or two point mutations, and two of these individuals carried the ex23_ex29del in their second allele. This mutation detection and mapping strategy provides a simple and reliable genetic assay to assist in diagnosis of PXE, differential diagnosis of PXE-like conditions, and study of PXE genetics. Mutations in the human ABCC6 gene cause pseudoxanthoma elasticum (PXE), a hereditary disorder that impacts the skin, eyes, and cardiovascular system. Currently, the diagnosis of PXE is based on physical findings and histological examination of a biopsy of affected skin. We have combined two simple, polymerase chain reaction (PCR)-based methods to develop a rapid, reliable genetic assay for the majority of known PXE mutations. After PCR amplification and heteroduplex formation, mutations in exon 24 and exon 28 of the ABCC6 gene were detected with Surveyor nuclease, which cleaves double-stranded DNA at any mismatch site. Mutations originating from deletion of a segment of the ABCC6 gene between exon 23 and exon 29 (ex23_ex29del) were detected by long-range PCR. Size analysis of digestion fragments and long-range PCR products was performed by agarose gel electrophoresis. The methods accurately identified mutations or the absence thereof in 16 affected individuals as confirmed by DNA sequencing. Fifteen patients had one or two point mutations, and two of these individuals carried the ex23_ex29del in their second allele. This mutation detection and mapping strategy provides a simple and reliable genetic assay to assist in diagnosis of PXE, differential diagnosis of PXE-like conditions, and study of PXE genetics. Pseudoxanthoma elasticum (PXE) is a human hereditary disorder of the ABCC6 gene (Online Mendelian Inheritance of Man no. 603234) that involves primarily the skin and eye, as well as occasionally the gastrointestinal and cardiovascular systems (Online Mendelian Inheritance of Man no. 264800). The characteristic clinical manifestations are the presence of yellowish papules and plaques leading to laxity and redundancy in flexural areas and angioid streaks in Bruch's membrane behind the retina, which is associated with choroidal neovascularization, hemorrhage, and subsequent central vision loss. Currently, diagnosis of PXE relies on clinical examination for characteristic skin lesions and angioid streaks or von Kossa staining of a biopsy of lesional skin looking for calcification of dystrophic dermal elastic fibers.1Lebwohl M Neldner K Pope FM De Paepe A Christiano AM Boyd CD Uitto J McKusick VA Classification of pseudoxanthoma elasticum: report of a consensus conference.J Am Acad Dermatol. 1994; 30: 103-107Abstract Full Text PDF PubMed Scopus (170) Google Scholar However, high individual variability in severity, phenotype, and disease onset and progression can complicate the diagnosis, even among affected siblings with identical mutations.2Hermes B Grutzkau A Hausser I Kunze J Henz BM Preclinical diagnosis of pseudoxanthoma elasticum—methodological restrictions and ethical problems.Eur J Dermatol. 2000; 10: 513-516PubMed Google Scholar There is a need for a definitive tool for diagnosis, particularly for siblings of affected individuals.The ABCC6 gene (Online Mendelian Inheritance of Man no. 603234) consists of 31 exons on human chromosome 16p13.1.3Struk B Neldner KH Rao VS St Jean P Lindpaintner K Mapping of both autosomal recessive and dominant variants of pseudoxanthoma elasticum to chromosome 16p13.1.Hum Mol Genet. 1997; 6: 1823-1828Crossref PubMed Scopus (110) Google Scholar4van Soest S Swart J Tijmes N Sandkuijl LA Rommers J Bergen AAB A locus for autosomal recessive pseudoxanthoma elasticum, with penetrance of vascular symptoms in carrier, maps to chromosome 16p13.1.Genome Res. 1997; 7: 830-834Crossref PubMed Scopus (69) Google Scholar5Le 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 Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum.Nat Genet. 2000; 25: 223-227Crossref PubMed Scopus (441) Google Scholar6Cai L Struk B Adams MD Ji W Haaf T Kang H-L Dho SE Xu X Ringpfeil F Nancarrow J Zäch S Schaen L Stumm M Niu T Chung J Lunze K Verrecchia B Goldsmith LA Viljoen D Figuera LE Fuchs W Lebwohl M Uitto J Richards R Hohl D Ramesar R Callen DF Kim U-J Doggett NA Neldner KH Lindpaintner K A 500-kb region on chromosome 16p13.1 contains the pseudoxanthoma elasticum locus: high-resolution mapping and genomic structure.J Mol Med. 2000; 78: 36-46Crossref PubMed Scopus (60) Google Scholar The gene encodes a protein (ABCC6/MRP6) belonging to the ATP-binding cassette membrane transporter family with 1503 amino acid residues, three transmembrane segments consisting of 17 hydrophobic helices, and two conserved nucleotide binding domains (NBD1 and NBD2).7Longhurst TJ O'Neill GM Harvie RM Davey RA The anthracycline resistance-associated (ara) gene, a novel gene associated with multidrug resistance in a human leukaemia cell line.Br J Cancer. 1996; 74: 1331-1335Crossref PubMed Scopus (56) Google Scholar8Belinsky MG Kruh GD MOAT-E (ARA) is a full-length MRP/cMOAT subfamily transporter expressed in kidney and liver.Br J Cancer. 1999; 80: 1342-1349Crossref PubMed Scopus (133) Google Scholar9Kool M van der Linden M de Haas M Baas F Borst P Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells.Cancer Res. 1999; 59: 175-182PubMed Google Scholar ABCC6 gene mutations have been associated with autosomal recessive and sporadic forms of PXE.5Le 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 Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum.Nat Genet. 2000; 25: 223-227Crossref PubMed Scopus (441) Google Scholar,10Struk B Cai L Zach S Ji W Chung J Lumsden A Stumm M Huber M Schaen L Kim CA Goldsmith LA Viljoen D Figuera LE Fuchs W Munier F Ramesar R Hohl D Richards R Neldner KH Lindpaintner K Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum.J Mol Med. 2000; 78: 282-286Crossref PubMed Scopus (110) Google Scholar11Ringpfeil F Lebwohl MG Christiano AM Uitto J Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter.Proc Natl Acad Sci USA. 2000; 97: 6001-6006Crossref PubMed Scopus (337) Google Scholar12Bergen 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 Mutations in ABCC6 cause pseudoxanthoma elasticum.Nat Genet. 2000; 25: 228-231Crossref PubMed Scopus (466) Google Scholar13Le Saux O Urban Z Goring HH Csiszar K Pope FM Richards AJ Pasquali-Ronchetti I Terry S Bercovitch L Lebwohl MG Breuning M van den Berg P Kornet L Ott J de Jong PTVM Bergen AAB Boyd CD Pseudoxanthoma elasticum maps to an 820-kb region of the p13.1 region of chromosome 16.Genomics. 1999; 62: 1-10Crossref PubMed Scopus (53) Google Scholar At present, some 150 causative mutations in this gene have been observed in different populations, with most mutations being missense, nonsense, deletion/insertion, or splice site alterations clustered toward the large carboxyl-terminal end of ABCC6/MRP6 in NBD1 and NBD2.5Le 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 Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum.Nat Genet. 2000; 25: 223-227Crossref PubMed Scopus (441) Google Scholar,10Struk B Cai L Zach S Ji W Chung J Lumsden A Stumm M Huber M Schaen L Kim CA Goldsmith LA Viljoen D Figuera LE Fuchs W Munier F Ramesar R Hohl D Richards R Neldner KH Lindpaintner K Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum.J Mol Med. 2000; 78: 282-286Crossref PubMed Scopus (110) Google Scholar11Ringpfeil F Lebwohl MG Christiano AM Uitto J Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter.Proc Natl Acad Sci USA. 2000; 97: 6001-6006Crossref PubMed Scopus (337) Google Scholar12Bergen 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 Mutations in ABCC6 cause pseudoxanthoma elasticum.Nat Genet. 2000; 25: 228-231Crossref PubMed Scopus (466) Google Scholar13Le Saux O Urban Z Goring HH Csiszar K Pope FM Richards AJ Pasquali-Ronchetti I Terry S Bercovitch L Lebwohl MG Breuning M van den Berg P Kornet L Ott J de Jong PTVM Bergen AAB Boyd CD Pseudoxanthoma elasticum maps to an 820-kb region of the p13.1 region of chromosome 16.Genomics. 1999; 62: 1-10Crossref PubMed Scopus (53) Google Scholar14Le 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 A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum.Am J Hum Genet. 2001; 69: 749-764Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar15Cai 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 A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: implications for mutation analysis in pseudoxanthoma elasticum.J Mol Med. 2001; 79: 536-546Crossref PubMed Scopus (45) Google Scholar16Ringpfeil F Nakano A Uitto J Pulkkinen L Compound heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma elasticum.Am J Hum Genet. 2001; 68: 642-652Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar17Meloni I Rubegni P De Aloe G Bruttini M Pianigiani E Cusano R Seri M Mondillo S Federico A Bardelli AM Andreassi L Fimiani M Renieri A Pseudoxanthoma elasticum: point mutations in the ABCC6 gene and a large deletion including also ABCC1 and MYH11.Hum Mutat. 2001; 18: 85Crossref PubMed Scopus (36) Google Scholar18Hu X Plomp A Wijnholds J Ten Brink J van Soest S van den Born LI Leys A Peek R de Jong PT Bergen AA ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum.Eur J Hum Genet. 2003; 11: 215-224Crossref PubMed Scopus (49) Google Scholar19Chassaing N Martin L Mazereeuw J Barrie L Nizard S Bonafe JL Calvas P Hovnanian A Novel ABCC6 mutations in pseudoxanthoma elasticum.J Invest Dermatol. 2004; 122: 608-613Crossref PubMed Scopus (73) Google Scholar20Gheduzzi D Guidetti R Anzivino C Tarugi P Di Leo E Quaglino D Ronchetti IP ABCC6 mutations in Italian families affected by pseudoxanthoma elasticum (PXE).Hum Mutat. 2004; 24: 438-439Crossref PubMed Scopus (54) Google Scholar21Miksch S Lumsden A Guenther UP Foernzler D Christen-Zach S Daugherty C Ramesar RS Lebwohl M Hohl D Neldner KH Lindpaintner K Richards RI Struk B Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6.Hum Mutat. 2005; 26: 235-248Crossref PubMed Scopus (83) Google Scholar22Chassaing N Martin L Calvas P Le Bert M Hovnanian A Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations.J Med Genet. 2005; 42: 881-892Crossref PubMed Scopus (235) Google Scholar23Hu X Peek R Plomp A ten Brink J Scheffer G van Soest S Leys A de Jong PT Bergen AA Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum.Invest Ophthalmol Vis Sci. 2003; 44: 1824-1829Crossref PubMed Scopus (34) Google Scholar24Hendig D Schulz V Eichgrun J Szliska C Gotting C Kleesiek K New ABCC6 gene mutations in German pseudoxanthoma elasticum patients.J Mol Med. 2005; 83: 140-147Crossref PubMed Scopus (30) Google Scholar25Hu S Plomp A Gorgels T Brink JT Loves W Mannens M de Jong PT Bergen AA Efficient molecular diagnostic strategy for ABCC6 in pseudoxanthoma elasticum.Genet Test. 2004; 8: 292-300Crossref PubMed Scopus (17) Google Scholar26Katona E Aslanidis C Remenyik E Csikos M Karpati S Paragh G Schmitz G Identification of a novel deletion in the ABCC6 gene leading to pseudoxanthoma elasticum.J Dermatol Sci. 2005; 40: 115-121Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar27Le Saux O Beck K Sachsinger C Treiber C Goring HH Curry K Johnson EW Bercovitch L Marais AS Terry SF Viljoen DL Boyd CD Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa.Hum Genet. 2002; 111: 331-338Crossref PubMed Scopus (28) Google Scholar28Noji Y Inazu A Higashikata T Nohara A Kawashiri MA Yu W Todo Y Nozue T Uno Y Hifumi S Mabuchi H Identification of two novel missense mutations (p.R1221C and p.R1357W) in the ABCC6(MRP6) gene in a Japanese patient with pseudoxanthoma elasticum (PXE).Intern Med. 2004; 43: 1171-1176Crossref PubMed Scopus (19) Google Scholar29Schulz V Hendig D Szliska C Gotting C Kleesiek K Novel mutations in the ABCC6 gene of German patients with pseudoxanthoma elasticum.Hum Biol. 2005; 77: 367-384Crossref PubMed Google Scholar30Schulz V Hendig D Henjakovic M Szliska C Kleesiek K Gotting C Mutational analysis of the ABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE).Hum Mutat. 2006; 27: 831Crossref PubMed Scopus (45) Google Scholar The most frequent mutations in North American, European, and South African populations are c.3421C>T (p.R1141X) in exon 24 and Alu-mediated deletion of sequences between exon 23 and 29 (ex23_ex29del).14Le 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 A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum.Am J Hum Genet. 2001; 69: 749-764Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar,16Ringpfeil F Nakano A Uitto J Pulkkinen L Compound heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma elasticum.Am J Hum Genet. 2001; 68: 642-652Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar,18Hu X Plomp A Wijnholds J Ten Brink J van Soest S van den Born LI Leys A Peek R de Jong PT Bergen AA ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum.Eur J Hum Genet. 2003; 11: 215-224Crossref PubMed Scopus (49) Google Scholar,19Chassaing N Martin L Mazereeuw J Barrie L Nizard S Bonafe JL Calvas P Hovnanian A Novel ABCC6 mutations in pseudoxanthoma elasticum.J Invest Dermatol. 2004; 122: 608-613Crossref PubMed Scopus (73) Google Scholar,21Miksch S Lumsden A Guenther UP Foernzler D Christen-Zach S Daugherty C Ramesar RS Lebwohl M Hohl D Neldner KH Lindpaintner K Richards RI Struk B Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6.Hum Mutat. 2005; 26: 235-248Crossref PubMed Scopus (83) Google Scholar,23Hu X Peek R Plomp A ten Brink J Scheffer G van Soest S Leys A de Jong PT Bergen AA Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum.Invest Ophthalmol Vis Sci. 2003; 44: 1824-1829Crossref PubMed Scopus (34) Google Scholar Mutations in the ABCC6 gene that cause PXE allow development of genetic tests for accurate clinical diagnosis, differential diagnosis from PXE-like phenotypes (eg, PXE-like papillary dermal elastolysis and fibroelastolytic papulosis, periumbilical perforating PXE, PXE-like presentation of β-thalassemia, and acquired PXE syndromes), and predictive preclinical diagnosis to allow for possible intervention and for timely genetic counseling.Surveyor nuclease is a member of the CEL DNA endonuclease family of enzymes that specifically cleaves mismatched base pairs in DNA heteroduplexes, including single-base substitutions, deletions, and insertions.31Oleykowski CA Bronson Mullins CR Godwin AK Yeung AT mutation detection using a novel plant endonuclease.Nucleic Acids Res. 1998; 26: 4597-4602Crossref PubMed Scopus (283) Google Scholar32Yang B Wen X Kodali NS Oleykowski CA Miller CG Kulinski J Besack D Yeung JA Kowalski D Yeung AT Purification, cloning, and characterization of the CEL I nuclease.Biochemistry. 2000; 39: 3533-3541Crossref PubMed Scopus (106) Google Scholar33Qiu P Shandilya H D'Alessio JM O'Connor K Durocher J Gerard GF Mutation detection using Surveyor nuclease.Biotechniques. 2004; 36: 702-707PubMed Google Scholar The mismatch-cutting activity of CEL nuclease family members has been used in a number of different applications designed to detect genetic variations.34Sokurenko EV Tchesnokova V Yeung AT Oleykowski CA Trintchina E Hughes KT Rashid RA Brint JM Moseley SL Lory S Detection of simple mutations and polymorphisms in large genomic regions.Nucleic Acids Res. 2001; 29: E111Crossref PubMed Scopus (45) Google Scholar35Till BJ Burtner C Comai L Henikoff S Mismatch cleavage by single-strand specific nucleases.Nucleic Acids Res. 2004; 32: 2632-2641Crossref PubMed Scopus (204) Google Scholar36Bannwarth S Procaccio V Paquis-Flucklinger V Surveyor nuclease: a new strategy for a rapid identification of heteroplasmic mitochondrial DNA mutations in patients with respiratory chain defects.Hum Mutat. 2005; 25: 575-582Crossref PubMed Scopus (59) Google Scholar37Greber B Tandara H Lehrach H Himmelbauer H Comparison of PCR-based mutation detection methods and application for identification of mouse Sult1a1 mutant embryonic stem cell clones using pooled templates.Hum Mutat. 2005; 25: 483-490Crossref PubMed Scopus (12) Google Scholar38Qiu P Shandilya H Gerard GF A method for clone sequence confirmation using a mismatch-specific DNA endonuclease.Mol Biotechnol. 2005; 29: 11-18Crossref PubMed Scopus (11) Google Scholar Here, we applied this technology to PXE genetic diagnosis in detection of mutations in exon 24 and exon 28 of the ABCC6 gene. In addition, we used long-range polymerase chain reaction (PCR) to identify ex23_ex29del mutations in the ABCC6 gene.16Ringpfeil F Nakano A Uitto J Pulkkinen L Compound heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma elasticum.Am J Hum Genet. 2001; 68: 642-652Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Agarose gel electrophoresis was used to analyze nuclease digestion products and long-range PCR products. The purpose of this study is to show that the combined use of these methods provides a simple and reliable test to screen for the most common disease-causing mutations in the ABCC6 gene.Materials and MethodsReagentsPrimers were custom synthesized by Invitrogen (Carlsbad, CA). Optimase polymerase, 10× Optimase reaction buffer, dNTPs, Surveyor Nuclease S, and TransOneK agarose were supplied by Transgenomic, Inc. (Omaha, NE).Patient Genomic DNA SamplesCoded patient genomic DNA samples were obtained from the PXE International/Genetic Alliance BioBank. PXE International is a not-for-profit foundation that initiates, conducts, and funds research on PXE. Donors were recruited by PXE International, underwent an informed decision-making process, and gave informed consent. The protocol was approved by the Genetic Alliance BioBank Institutional Review Board. Donors were considered positive for PXE if they met at least two of the following three conditions: skin biopsy demonstrating calcification of dystrophic elastic fibers in the dermis, the presence of angioid streaks in the retina, or positive family history of PXE.39Uitto J Boyd CD Lebwohl MG Moshell AN Rosenbloom J Terry S International Centennial Meeting on pseudoxanthoma elasticum: progress in PXE research.J Invest Dermatol. 1998; 110: 840-842Crossref PubMed Scopus (45) Google Scholar Genomic DNA was isolated from whole blood (Puregene DNA isolation kit; Gentra Systems, Minneapolis, MN). Normal genomic DNA was obtained from the human cell line K562 (American Type Culture Collection, Manassas, VA). Coded samples were each randomly assigned numbers from 1 to 16 for identification purposes. Blinded analyses for nuclease assay and long-range PCR were performed on this DNA set.ABCC6 Mutations Selected for AnalysisStudies of cohorts from North America, Europe, and other populations have identified ∼150 disease-causing mutations in the ABCC6 gene.5Le 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 Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum.Nat Genet. 2000; 25: 223-227Crossref PubMed Scopus (441) Google Scholar,10Struk B Cai L Zach S Ji W Chung J Lumsden A Stumm M Huber M Schaen L Kim CA Goldsmith LA Viljoen D Figuera LE Fuchs W Munier F Ramesar R Hohl D Richards R Neldner KH Lindpaintner K Mutations of the gene encoding the transmembrane transporter protein ABC-C6 cause pseudoxanthoma elasticum.J Mol Med. 2000; 78: 282-286Crossref PubMed Scopus (110) Google Scholar11Ringpfeil F Lebwohl MG Christiano AM Uitto J Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter.Proc Natl Acad Sci USA. 2000; 97: 6001-6006Crossref PubMed Scopus (337) Google Scholar12Bergen 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 Mutations in ABCC6 cause pseudoxanthoma elasticum.Nat Genet. 2000; 25: 228-231Crossref PubMed Scopus (466) Google Scholar13Le Saux O Urban Z Goring HH Csiszar K Pope FM Richards AJ Pasquali-Ronchetti I Terry S Bercovitch L Lebwohl MG Breuning M van den Berg P Kornet L Ott J de Jong PTVM Bergen AAB Boyd CD Pseudoxanthoma elasticum maps to an 820-kb region of the p13.1 region of chromosome 16.Genomics. 1999; 62: 1-10Crossref PubMed Scopus (53) Google Scholar14Le 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 A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum.Am J Hum Genet. 2001; 69: 749-764Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar15Cai 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 A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: implications for mutation analysis in pseudoxanthoma elasticum.J Mol Med. 2001; 79: 536-546Crossref PubMed Scopus (45) Google Scholar16Ringpfeil F Nakano A Uitto J Pulkkinen L Compound heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma elasticum.Am J Hum Genet. 2001; 68: 642-652Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar17Meloni I Rubegni P De Aloe G Bruttini M Pianigiani E Cusano R Seri M Mondillo S Federico A Bardelli AM Andreassi L Fimiani M Renieri A Pseudoxanthoma elasticum: point mutations in the ABCC6 gene and a large deletion including also ABCC1 and MYH11.Hum Mutat. 2001; 18: 85Crossref PubMed Scopus (36) Google Scholar18Hu X Plomp A Wijnholds J Ten Brink J van Soest S van den Born LI Leys A Peek R de Jong PT Bergen AA ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum.Eur J Hum Genet. 2003; 11: 215-224Crossref PubMed Scopus (49) Google Scholar19Chassaing N Martin L Mazereeuw J Barrie L Nizard S Bonafe JL Calvas P Hovnanian A Novel ABCC6 mutations in pseudoxanthoma elasticum.J Invest Dermatol. 2004; 122: 608-613Crossref PubMed Scopus (73) Google Scholar20Gheduzzi D Guidetti R Anzivino C Tarugi P Di Leo E Quaglino D Ronchetti IP ABCC6 mutations in Italian families affected by pseudoxanthoma elasticum (PXE).Hum Mutat. 2004; 24: 438-439Crossref PubMed Scopus (54) Google Scholar21Miksch S Lumsden A Guenther UP Foernzler D Christen-Zach S Daugherty C Ramesar RS Lebwohl M Hohl D Neldner KH Lindpaintner K Richards RI Struk B Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6.Hum Mutat. 2005; 26: 235-248Crossref PubMed Scopus (83) Google Scholar22Chassaing N Martin L Calvas P Le Bert M Hovnanian A Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations.J Med Genet. 2005; 42: 881-892Crossref PubMed Scopus (235) Google Scholar23Hu X Peek R Plomp A ten Brink J Scheffer G van Soest S Leys A de Jong PT Bergen AA Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum.Invest Ophthalmol Vis Sci. 2003; 44: 1824-1829Crossref PubMed Scopus (34) Google Scholar24Hendig D Schulz V Eichgrun J Szliska C Gotting C Kleesiek K New ABCC6 gene mutations in German pseudoxanthoma elasticum patients.J Mol Med. 2005; 83: 140-147Crossref PubMed Scopus (30) Google Scholar25Hu S Plomp A Gorgels T Brink JT Loves W Mannens M de Jong PT Bergen AA Efficient molecular diagnostic strategy for ABCC6 in pseudoxanthoma elasticum.Genet Test. 2004; 8: 292-300Crossref PubMed Scopus (17) Google Scholar26Katona E Aslanidis C Remenyik E Csikos M Karpati S Paragh G Schmitz G Identification of a novel deletion in the ABCC6 gene leading to pseudoxanthoma elasticum.J Dermatol Sci. 2005; 40: 115-121Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar27Le Saux O Beck K Sachsinger C Treiber C Goring HH Curry K Johnson EW Bercovitch L Marais AS Terry SF Viljoen DL Boyd CD Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa.Hum Genet. 2002; 111: 331-338Crossref PubMed Scopus (28) Google Scholar28Noji Y Inazu A Higashikata T Nohara A Kawashiri MA Yu W Todo Y Nozue T Uno Y Hifumi S Mabuchi H Identification of two novel missense mutations (p.R1221C and p.R1357W) in the ABCC6(MRP6) gene in a Japanese patient with pseudoxanthoma elasticum (PXE).Intern Med. 2004; 43: 1171-1176Crossref PubMed Scopus (19) Google Scholar29Schulz V Hendig D Szliska C Gotting C Kleesiek K Novel mutations in the ABCC6 gene of German patients with pseudoxanthoma elasticum.Hum Biol. 2005; 77: 367-384Crossref PubMed Google Scholar30Schulz V Hendig D Henjakovic M Szliska C Kleesiek K Gotting C Mutational analysis of the ABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE).Hum Mutat. 2006; 27: 831Crossref PubMed Scopus (45) Google Scholar Whereas neutral variants are evenly distributed, pathogenic mutations are clustered at the downstream end of the ABCC6 gene, particularly in exon 24 and in exons 28 to 30. 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