title: Mutations in the ABCC6 gene as a cause of generalized arterial calcification of infancy: genotypic overlap with pseudoxanthoma elasticum.
abstract: Generalized arterial calcification of infancy (GACI) is an autosomal recessive disorder characterized by congenital calcification of large- and medium-sized arteries, associated with early myocardial infarction, heart failure, and stroke, and premature death. Most cases of GACI are caused by mutations in the ENPP1 gene. We first studied two siblings with GACI from a non-consanguineous family without mutations in the ENPP1 gene. To search for disease-causing mutations, we identified genomic regions shared between the two affected siblings but not their unaffected parents or brother. The ABCC6 gene, which is mutated in pseudoxanthoma elasticum (PXE), resided within a small region of homozygosity shared by the affected siblings. Sequence analysis of ABCC6 revealed that the two affected siblings were homozygous for the missense mutation p.R1314W. Subsequently, ABCC6 mutations were identified in five additional GACI families with normal ENPP1 sequences. Genetic mutations in ABCC6 in patients with PXE are associated with ectopic tissue mineralization in the skin and arterial blood vessels. Thus, our findings provide additional evidence that the ABCC6 gene product inhibits calcification under physiologic conditions and confirm a second locus for GACI. In addition, our study emphasizes the potential utility of shared homozygosity mapping to identify genetic causes of inherited disorders.
authors.affiliation: Departments of Dermatology and Cutaneous Biology, and Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Li
authors.affiliation: Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Jill L
authors.initials: JL
authors.lastname: Brodsky
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Laura K
authors.initials: LK
authors.lastname: Conlin
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Pawel
authors.affiliation: Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Glatz
authors.affiliation: National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Rachel I
authors.initials: RI
authors.lastname: Gafni
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Leon
authors.initials: L
authors.lastname: Schurgers
authors.affiliation: Departments of Dermatology and Cutaneous Biology, and Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.affiliation: Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA; Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
authors.affiliation: Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address: levinem@chop.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Levine
mesh_terms: D000328:Adult; D001158:Arteries / Q000473:pathology / Q000502:physiology; D005192:Family Health; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D011561:Pseudoxanthoma Elasticum / Q000235:genetics* / Q000473:pathology; D035781:Siblings; D061205:Vascular Calcification / Q000235:genetics* / Q000473:pathology
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; C102029:ABCC6 protein, human