Autosomal recessive mental retardation, deafness, ankylosis, and mild hypophosphatemia associated with a novel ANKH mutation in a consanguineous family

Eva Morava-Kozicz, Jirko Kühnisch, Jefte M. Drijvers, Joris H. Robben, Cor Cremers, Petra Van Setten, Amanda Branten, Sabine Stumpp, Alphons De Jong, Krysta Voesenek, Sascha Vermeer, Angelien Heister, Hedi L. Claahsen-Van Der Grinten, Charles W. O'Neill, Michèl A. Willemsen, Dirk Lefeber, Peter M.T. Deen, Uwe Kornak, Hannie Kremer, Ron A. Wevers

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

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)mousemutant. 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.

Original languageEnglish (US)
JournalJournal of Clinical Endocrinology and Metabolism
Volume96
Issue number1
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

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Hypophosphatemia
Ankylosis
Deafness
Intellectual Disability
Joints
Tissue
Mutation
Neurology
Genes
Central Nervous System
Mixed Conductive-Sensorineural Hearing Loss
Chondrocalcinosis
Audition
Phenotype
Fibroblasts
Cell membranes
Spondylarthropathies
Metabolic Bone Diseases
Chromosome Mapping
Extracellular Space

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Autosomal recessive mental retardation, deafness, ankylosis, and mild hypophosphatemia associated with a novel ANKH mutation in a consanguineous family. / Morava-Kozicz, Eva; Kühnisch, 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, Michèl A.; Lefeber, Dirk; Deen, Peter M.T.; Kornak, Uwe; Kremer, Hannie; Wevers, Ron A.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 96, No. 1, 01.01.2011.

Research output: Contribution to journalArticle

Morava-Kozicz, E, Kühnisch, J, Drijvers, JM, Robben, JH, Cremers, C, Van Setten, P, Branten, A, Stumpp, S, De Jong, A, Voesenek, K, Vermeer, S, Heister, A, Claahsen-Van Der Grinten, HL, O'Neill, CW, Willemsen, MA, Lefeber, D, Deen, PMT, Kornak, U, Kremer, H & Wevers, RA 2011, 'Autosomal recessive mental retardation, deafness, ankylosis, and mild hypophosphatemia associated with a novel ANKH mutation in a consanguineous family', Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 1. https://doi.org/10.1210/jc.2010-1539
Morava-Kozicz, Eva ; Kühnisch, 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, Michèl A. ; Lefeber, Dirk ; Deen, Peter M.T. ; Kornak, Uwe ; Kremer, Hannie ; Wevers, Ron A. / Autosomal recessive mental retardation, deafness, ankylosis, and mild hypophosphatemia associated with a novel ANKH mutation in a consanguineous family. In: Journal of Clinical Endocrinology and Metabolism. 2011 ; Vol. 96, No. 1.
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T1 - Autosomal recessive mental retardation, deafness, ankylosis, and mild hypophosphatemia associated with a novel ANKH mutation in a consanguineous family

AU - Morava-Kozicz, Eva

AU - Kühnisch, Jirko

AU - Drijvers, Jefte M.

AU - Robben, Joris H.

AU - Cremers, Cor

AU - Van Setten, Petra

AU - Branten, Amanda

AU - Stumpp, Sabine

AU - De Jong, Alphons

AU - Voesenek, Krysta

AU - Vermeer, Sascha

AU - Heister, Angelien

AU - Claahsen-Van Der Grinten, Hedi L.

AU - O'Neill, Charles W.

AU - Willemsen, Michèl A.

AU - Lefeber, Dirk

AU - Deen, Peter M.T.

AU - Kornak, Uwe

AU - Kremer, Hannie

AU - Wevers, Ron A.

PY - 2011/1/1

Y1 - 2011/1/1

N2 - 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)mousemutant. 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.

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