Autosomal Recessive Mental Retardation, Deafness, Ankylosis, and Mild Hypophosphatemia Associated with a Novel ANKH Mutation in a Consanguineous Family

作者：Morava Eva^*; Kuehnisch Jirko; Drijvers Jefte M; Robben Joris H; Cremers Cor; van Setten Petra; Branten Amanda; Stumpp Sabine; de Jong Alphons; Voesenek Krysta; Vermeer Sascha; Heister Angelien; Claahsen van der Grinten Hedi L; O'Neill Charles W; Willemsen Michel A; Lefeber Dirk; Deen Peter M T; Kornak Uwe; Kremer Hannie; Wevers Ron A

来源：Journal of Clinical Endocrinology & Metabolism, 2011, 96(1): E189-E198.

DOI：10.1210/jc.2010-1539

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 L2445 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 L2445 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. (J Clin Endocrinol Metab 96: E189-E198, 2011)

• 出版日期2011-1
• 单位河北医科大学