title: Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum.
abstract: BACKGROUND
  Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 (ATP binding cassette family C member 6) gene, which encodes MRP6 (multidrug resistance-associated protein 6).
  
  
  OBJECTIVE
  To investigate the mutation spectrum of ABCC6 and possible genotype-phenotype correlations.
  
  
  METHODS
  Mutation data were collected on an international case series of 270 patients with PXE (239 probands, 31 affected family members). A denaturing high-performance liquid chromatography-based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype-phenotype correlations were assessed.
  
  
  RESULTS
  In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were found to cluster 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 and del23-29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype-phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease.
  
  
  CONCLUSIONS
  This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.
authors.affiliation: GeneDx Inc., 207 Perry Parkway, Gaithersburg, Maryland 20877, USA. ellen@genedx.com
authors.forename: Ellen G
authors.initials: EG
authors.lastname: Pfendner
authors.forename: Olivier M
authors.initials: OM
authors.lastname: Vanakker
authors.forename: Sharon F
authors.initials: SF
authors.lastname: Terry
authors.forename: Sophia
authors.initials: S
authors.lastname: Vourthis
authors.forename: Patricia E
authors.initials: PE
authors.lastname: McAndrew
authors.forename: Monica R
authors.initials: MR
authors.lastname: McClain
authors.forename: Sarah
authors.initials: S
authors.lastname: Fratta
authors.forename: Anna-Susan
authors.initials: AS
authors.lastname: Marais
authors.forename: Susan
authors.initials: S
authors.lastname: Hariri
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coucke
authors.forename: Michele
authors.initials: M
authors.lastname: Ramsay
authors.forename: Denis
authors.initials: D
authors.lastname: Viljoen
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Terry
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.forename: Lionel G
authors.initials: LG
authors.lastname: Bercovitch
mesh_terms: D000483:Alleles; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003062:Codon; D004252:DNA Mutational Analysis; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D007391:International Cooperation; D008957:Models, Genetic; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011561:Pseudoxanthoma Elasticum / Q000235:genetics* / Q000473:pathology*; D012871:Skin Diseases / Q000235:genetics / Q000473:pathology
chemical_list: D003062:Codon; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C102029:ABCC6 protein, human