Mutations in ANKH cause chondrocalcinosis.
Chondrocalcinosis (CC) is a common cause of joint pain and arthritis that is caused by the deposition of calcium-containing crystals within articular cartilage. Although most cases are sporadic, rare familial forms have been linked to human chromosomes 8 (CCAL1) or 5p (CCAL2) (Baldwin et al. 1995; Hughes et al. 1995; Andrew et al. 1999). Here, we show that two previously described families with CCAL2 have mutations in the human homolog of the mouse progressive ankylosis gene (ANKH). One of the human mutations results in the substitution of a highly conserved amino acid residue within a predicted transmembrane segment. The other creates a new ATG start site that adds four additional residues to the ANKH protein. Both mutations segregate completely with disease status and are not found in control subjects. In addition, 1 of 95 U.K. patients with sporadic CC showed a deletion of a single codon in the ANKH gene. The same change was found in a sister who had bilateral knee replacement for osteoarthritis. Each of the three human mutations was reconstructed in a full-length ANK expression construct previously shown to regulate pyrophosphate levels in cultured cells in vitro. All three of the human mutations showed significantly more activity than a previously described nonsense mutation that causes severe hydroxyapatite mineral deposition and widespread joint ankylosis in mice. These results suggest that small sequence changes in ANKH are one cause of CC and joint disease in humans. Increased ANK activity may explain the different types of crystals commonly deposited in human CCAL2 families and mutant mice and may provide a useful pharmacological target for treating some forms of human CC.
Pendleton
Adrian
A
Department of Medical Genetics, The Queen's University of Belfast, United Kingdom.
Johnson
Michelle D
MD
Hughes
Anne
A
Gurley
Kyle A
KA
Ho
Andrew M
AM
Doherty
Michael
M
Dixey
Josh
J
Gillet
Pierre
P
Loeuille
Damien
D
McGrath
Rodney
R
Reginato
Antonio
A
Shiang
Rita
R
Wright
Gary
G
Netter
Patrick
P
Williams
Charlene
C
Kingsley
David M
DM
D002478:Cells, Cultured; D002805:Chondrocalcinosis / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D028061:Phosphate Transport Proteins; D017422:Sequence Analysis, DNA
C498770:ANKH protein, human; D008565:Membrane Proteins; D028061:Phosphate Transport Proteins