Abstract
A 16-year-old male patient with type II autosomal dominant benign osteopetrosis (ADO) was genotyped and found to harbor a novel mutation in exon 25 of the gene encoding for the osteoclast-specific chloride channel, CLCN7, inherited from the father, who was asymptomatic. The patient had normal biochemical findings and acid-base balance, except for increased serum levels of creatine kinase, lactic dehydrogenase, and the bone formation markers bone alkaline phosphatase isoenzyme, osteocalcin and N-terminal type I collagen telopeptide/creatinine ratio. Unusual generalized osteosclerosis was observed together with a canonical increase in vertebral and pelvis bone mass. An affected first grade cousin presented with normal biochemical findings and a milder osteosclerotic pattern of the pelvis. At the cellular level, cultured osteoclasts from the patient showed increased motility, with lamellipodia, membrane ruffling and motile pattern of podosome distribution, all of which could have contributed to functional impairment of bone resorption. The present report documents a novel mutation of the CLCN7 gene causing osteopetrosis in a radiologically uncertain form of the diseases, with apparent incomplete penetrance.
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References
MP Whyte (2002) Osteopetrosis. PM Royce B Steinmann (Eds) Connective tissue and its heritable disorders: medical, genetic, and molecular aspects, 2nd ed. Wiley-Liss New York 753–770
J Bollerslev PE Anderson Jr (1988) ArticleTitleRadiological, biochemical and hereditary evidence of two types of autosomal dominant osteopetrosis. Bone 91 7–13
L Van Wesenbeeck E Cleiren J Gram et al. (2003) ArticleTitleSix novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet 72 763–771 Occurrence Handle10.1086/368277 Occurrence Handle1:CAS:528:DC%2BD3sXitFajs7Y%3D Occurrence Handle12579474
O Bénichou JD Laredo MC de Vernejoul (2000) ArticleTitleType II autosomal dominant osteopetrosis (Albers-Schönberg disease): clinical and radiological manifestations in 42 patients. Bone 26 87–93 Occurrence Handle1:STN:280:DC%2BD3c%2FotlCmsw%3D%3D Occurrence Handle10617161
E Cleiren O Benichou E Van Hul et al. (2001) ArticleTitleAlbers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the CLCN7 chloride channel gene. Hum Mol Genet 10 2861–2867 Occurrence Handle1:CAS:528:DC%2BD38XjtVegtg%3D%3D Occurrence Handle11741829
A-V Rousselle D Heymann (2002) ArticleTitleOsteoclastic acidification pathways during bone resorption. Bone 30 533–540 Occurrence Handle10.1016/S8756-3282(02)00672-5 Occurrence Handle1:CAS:528:DC%2BD38XisV2ksL8%3D Occurrence Handle11934642
G Stenbeck (2002) ArticleTitleFormation and function of the ruffled border in osteoclasts. Cell Dev Biol 13 285–292 Occurrence Handle10.1016/S1084952102000587 Occurrence Handle1:CAS:528:DC%2BD38XntVanu7w%3D
U Kornak D Kasper MR Bosl E Kaiser M Schweizer A Schulz W Friedrich G Delling TJ Jentsch (2001) ArticleTitleLoss of the CIC-7 chloride channel leads to osteopetrosis in mice and man. Cell 104 205–215 Occurrence Handle1:CAS:528:DC%2BD3MXis1Kmu7s%3D Occurrence Handle11207362
A Frattini PJ Orchard C Sobacchi et al. (2000) ArticleTitleDefects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nature Genet 25 343–346 Occurrence Handle10.1038/77131 Occurrence Handle1:CAS:528:DC%2BD3cXkvFKktLo%3D Occurrence Handle10888887
WS Sly PY Hu (1995) The carbonic anhydrase II deficiency syndrome: osteopetrosis with renal tubular acidosis and cerebral calcification. CR Scriver AL Beaudet WS Sly D Valle (Eds) The metabolic and molecular bases of inherited diseases, 7th ed, McGraw-Hill New York 4113–4124
KJ Borthwick N Kandemir R Topaloglu et al. (2003) ArticleTitleA phenocopy of CAII deficiency: a novel genetic explanation of inherited infantile osteopetrosis with distal tubular acidosis. J Med Genet 40 115–121 Occurrence Handle10.1136/jmg.40.2.115 Occurrence Handle1:CAS:528:DC%2BD3sXhslOgsLo%3D Occurrence Handle12566520
M Marzia NA Sims S Voit et al. (2000) ArticleTitleDecreased c-Src expression enhances osteoblast differentiation and bone formation. J Cell Biol 151 311–320 Occurrence Handle10.1083/jcb.151.2.311 Occurrence Handle1:CAS:528:DC%2BD3cXnsVaqsL0%3D Occurrence Handle11038178
M Zaidi HC Blair BS Moonga E Abe CL-H Huang (2003) ArticleTitleOsteoclastogenesis, bone resorption, and osteoclast-based therapeutics. J Bone Miner Res 18 599–609
JE Aubin (1992) ArticleTitleOsteoclast adhesion and resorption: the role of podosomes. J Bone Miner Res 7 365–368
A Teti PC Marchisio AZ Zallone (1991) ArticleTitleClear zone in osteoclast function: role of podosomes in regulation of bone-resorbing activity. Am J Physiol . C1–C7
A Taranta S Migliaccio I Recchia et al. (2003) ArticleTitleGenotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis. Am J Pathol 162 57–68 Occurrence Handle1:CAS:528:DC%2BD3sXlsFyruw%3D%3D Occurrence Handle12507890
Acknowledgements
We thank Prof. Paolo Menè for helpful discussions. The Telethon grant #E.0831 and the “Fondo per gli Investimenti per la Ricerca di Base” (FIRB) grant #RBAU01X3NH to A.T. are gratefully acknowledged.
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Letizia, C., Taranta, A., Migliaccio, S. et al. Type II Benign Osteopetrosis (Albers-Schönberg Disease) Caused by a Novel Mutation in CLCN7 Presenting with Unusual Clinical Manifestations . Calcif Tissue Int 74, 42–46 (2004). https://doi.org/10.1007/s00223-002-1087-5
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DOI: https://doi.org/10.1007/s00223-002-1087-5