CONTEXT: Mutations in ANKH cause the highly divergent conditions familial chondrocalcinosis and craniometaphyseal dysplasia. The gene product ANK is supposed to regulate tissue mineralization by transporting pyrophosphate to the extracellular space. OBJECTIVE: We evaluated several family members of a large consanguineous family with mental retardation, deafness, and ankylosis. We compared their skeletal, metabolic, and serological parameters to that of the autosomal recessive progressive ankylosis (ank) mouse mutant, caused by a loss-of-function mutation in the murine ortholog Ank. PARTICIPANTS: The studied patients had painful small joint soft-tissue calcifications, progressive spondylarthropathy, osteopenia, mild hypophosphatemia, mixed hearing loss, and mental retardation. RESULTS: After mapping the disease gene to 5p15, we identified the novel homozygous ANK missense mutation L244S in all patients. Although L244 is a highly conserved amino acid, the mutated ANK protein was detected at normal levels at the plasma membrane in primary patient fibroblasts. The phenotype was highly congruent with the autosomal recessive progressive ankylosis (ank) mouse mutant. This indicates a loss-of-function effect of the L244S mutation despite normal ANK protein expression. Interestingly, our analyses revealed that the primary step of joint degeneration is fibrosis and mineralization of articular soft tissues. Moreover, heterozygous carriers of the L244S mutation showed mild osteoarthritis without metabolic alterations, pathological calcifications, or central nervous system involvement. CONCLUSION: Beyond the description of the first human progressive ankylosis phenotype, our results indicate that ANK influences articular soft tissues commonly involved in degenerative joint disorders. Furthermore, this human disorder provides the first direct evidence for a role of ANK in the central nervous system.
CONTEXT: Mutations in ANKH cause the highly divergent conditions familial chondrocalcinosis and craniometaphyseal dysplasia. The gene product ANK is supposed to regulate tissue mineralization by transporting pyrophosphate to the extracellular space. OBJECTIVE: We evaluated several family members of a large consanguineous family with mental retardation, deafness, and ankylosis. We compared their skeletal, metabolic, and serological parameters to that of the autosomal recessive progressive ankylosis (ank) mouse mutant, caused by a loss-of-function mutation in the murine ortholog Ank. PARTICIPANTS: The studied patients had painful small joint soft-tissue calcifications, progressive spondylarthropathy, osteopenia, mild hypophosphatemia, mixed hearing loss, and mental retardation. RESULTS: After mapping the disease gene to 5p15, we identified the novel homozygous ANK missense mutation L244S in all patients. Although L244 is a highly conserved amino acid, the mutated ANK protein was detected at normal levels at the plasma membrane in primary patient fibroblasts. The phenotype was highly congruent with the autosomal recessive progressive ankylosis (ank) mouse mutant. This indicates a loss-of-function effect of the L244S mutation despite normal ANK protein expression. Interestingly, our analyses revealed that the primary step of joint degeneration is fibrosis and mineralization of articular soft tissues. Moreover, heterozygous carriers of the L244S mutation showed mild osteoarthritis without metabolic alterations, pathological calcifications, or central nervous system involvement. CONCLUSION: Beyond the description of the first human progressive ankylosis phenotype, our results indicate that ANK influences articular soft tissues commonly involved in degenerative joint disorders. Furthermore, this human disorder provides the first direct evidence for a role of ANK in the central nervous system.
Authors: P Nürnberg; H Thiele; D Chandler; W Höhne; M L Cunningham; H Ritter; G Leschik; K Uhlmann; C Mischung; K Harrop; J Goldblatt; Z U Borochowitz; D Kotzot; F Westermann; S Mundlos; H S Braun; N Laing; S Tinschert Journal: Nat Genet Date: 2001-05 Impact factor: 38.330
Authors: Peter M T Deen; Bas W M Van Balkom; Paul J M Savelkoul; Erik-Jan Kamsteeg; Marcel Van Raak; Michael L Jennings; Theodoor R Muth; Vanathy Rajendran; Michael J Caplan Journal: Am J Physiol Renal Physiol Date: 2002-02
Authors: Charlene J Williams; Yun Zhang; Andrew Timms; Gina Bonavita; Francisco Caeiro; John Broxholme; Jonathan Cuthbertson; Yvonne Jones; Raul Marchegiani; Antonio Reginato; R Graham G Russell; B Paul Wordsworth; Andrew J Carr; Matthew A Brown Journal: Am J Hum Genet Date: 2002-09-17 Impact factor: 11.025
Authors: David J Brown; Theresa B Kim; Elizabeth M Petty; Catherine A Downs; Donna M Martin; Peter J Strouse; Sayoko E Moroi; Jeff M Milunsky; Marci M Lesperance Journal: Am J Hum Genet Date: 2002-06-27 Impact factor: 11.025
Authors: Barry L Gruber; Ana Rita Couto; Jácome Bruges Armas; Matthew A Brown; Kathleen Finzel; Robert A Terkeltaub Journal: J Clin Rheumatol Date: 2012-06 Impact factor: 3.517
Authors: B L Foster; K J Nagatomo; S O Bamashmous; K A Tompkins; H Fong; D Dunn; E Y Chu; C Guenther; D M Kingsley; R B Rutherford; M J Somerman Journal: Cells Tissues Organs Date: 2011-03-09 Impact factor: 2.481