title: Cuff tear arthropathy: evidence of functional variation in pyrophosphate metabolism genes.
abstract: We investigated the role of two genes, ANKH and TNAP, in patients with cuff tear arthropathy. These genes encode proteins which regulate the extracellular concentration of inorganic pyrophosphate, fluctuations of which can lead to calcium crystal formation. Variants were detected by direct sequencing of DNA and their frequencies compared with healthy controls. The effect of variants on protein function was further studied by in vitro approaches. Variant genotypes were observed more frequently in the cases when compared with controls in ANKH (45% and 20%) and TNAP (32% and 9%). Variants in ANKH altered inorganic pyrophosphate (PPi) concentrations in transfected human chondrocytes. There was a higher mean serum concentration of TNAP detected in female patients compared with normal ranges. Cuff tear arthropathy is associated with variants in ANKH and TNAP that alter extracellular inorganic pyrophosphate concentrations causing calcium crystal deposition. This supports a theory that genetic variants predispose patients to primary crystal deposition which when combined with a massive rotator cuff tear leads to the development of arthritis.
authors.affiliation: Nuffield Department of Orthopaedic Surgery, University of Oxford, Headington, Oxford, England. c.peach@doctors.org.uk
authors.forename: Chris A
authors.initials: CA
authors.lastname: Peach
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: James E
authors.initials: JE
authors.lastname: Dunford
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Carr
mesh_terms: D000469:Alkaline Phosphatase; D002352:Carrier Proteins / Q000097:blood / Q000235:genetics*; D002478:Cells, Cultured; D002805:Chondrocalcinosis / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism; D011756:Diphosphates / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D028061:Phosphate Transport Proteins / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D000070636:Rotator Cuff Injuries; D017422:Sequence Analysis, DNA; D012737:Sex Factors; D012785:Shoulder Joint / Q000378:metabolism / Q000473:pathology*; D014162:Transfection
chemical_list: C498770:ANKH protein, human; D002352:Carrier Proteins; D011756:Diphosphates; D028061:Phosphate Transport Proteins; C548267:ALPL protein, human; D000469:Alkaline Phosphatase