{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T04:48:45Z","timestamp":1782449325195,"version":"3.54.5"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2013,9,23]],"date-time":"2013-09-23T00:00:00Z","timestamp":1379894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,4,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Osteopetrosis is an inherited disorder of impaired bone resorption, with the most commonly affected genes being CLCN7 and TCIRG1, encoding the Cl\u2212\/H+ exchanger CLC-7 and the a3 subunit of the vacuolar H+-ATPase, respectively. We and others have previously shown that the disease is frequently accompanied by osteomalacia, and that this additional pathology is also found in Tcirg1-deficient oc\/oc mice. The remaining question was whether osteoid enrichment is specifically associated with TCIRG1 inactivation, or whether CLCN7 mutations would also cause skeletal mineralization defects. Here we describe a complete osteologic assessment of one family carrying a novel mutation in CLCN7 (D145G), which impairs the activation and relaxation kinetics of the CLC-7 ion transporter. The two siblings carrying the mutation in the homozygous state displayed high bone mass, increased serum levels of bone formation markers, but no impairment of calcium homeostasis when compared to the other family members. Most importantly, however, undecalcified processing of an iliac crest biopsy from one of the affected children clearly demonstrated a pathological increase of trabecular bone mass, but no signs of osteomalacia. Given the potential relevance of these findings we additionally performed undecalcified histology of iliac crest biopsies from seven additional cases with osteopetrosis caused by a mutation in TNFRSF11A (n\u2009=\u20091), CLCN7 (n\u2009=\u20093), or TCIRG1 (n\u2009=\u20093). Here we observed that all cases with TCIRG1-dependent osteopetrosis displayed severe osteoid accumulation and decreased calcium content within the mineralized matrix. In contrast, there was no detectable bone mineralization defect in the cases with TNFRSF11A-dependent or CLCN7-dependent osteopetrosis. Taken together, our analysis demonstrates that CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization, and that there is a need to modify the current classification of osteopetrosis. \u00a9 2014 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2100","type":"journal-article","created":{"date-parts":[[2013,10,12]],"date-time":"2013-10-12T00:59:31Z","timestamp":1381539571000},"page":"982-991","source":"Crossref","is-referenced-by-count":47,"title":["<i>CLCN7<\/i> and <i>TCIRG1<\/i> Mutations Differentially Affect Bone Matrix Mineralization in Osteopetrotic Individuals"],"prefix":"10.1093","volume":"29","author":[{"given":"Florian","family":"Barvencik","sequence":"first","affiliation":[{"name":"Department of Osteology and BiomechanicsUniversity Medical Center Hamburg-EppendorfHamburgGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Kurth","sequence":"additional","affiliation":[{"name":"Department of Human GeneticsJena University HospitalJenaGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Till","family":"Koehne","sequence":"additional","affiliation":[{"name":"Department of Osteology and BiomechanicsUniversity Medical Center Hamburg-EppendorfHamburgGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Stauber","sequence":"additional","affiliation":[{"name":"Physiology and Pathology of Ion TransportLeibniz-Institut f\u00fcr Molekulare Pharmakologie (FMP) and Max-Delbr\u00fcck-Centrum f\u00fcr Molekulare Medizin (MDC)BerlinGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jozef","family":"Zustin","sequence":"additional","affiliation":[{"name":"Institute of PathologyUniversity Medical Center Hamburg-EppendorfHamburgGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Tsiakas","sequence":"additional","affiliation":[{"name":"Department of PediatricsUniversity Medical Center Hamburg-EppendorfHamburgGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen F","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Physiology and Pathology of Ion TransportLeibniz-Institut f\u00fcr Molekulare Pharmakologie (FMP) and Max-Delbr\u00fcck-Centrum f\u00fcr Molekulare Medizin (MDC)BerlinGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F Timo","family":"Beil","sequence":"additional","affiliation":[{"name":"Department of Osteology and BiomechanicsUniversity Medical Center Hamburg-EppendorfHamburgGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan M","family":"Pestka","sequence":"additional","affiliation":[{"name":"Department of Osteology and BiomechanicsUniversity Medical Center Hamburg-EppendorfHamburgGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hahn","sequence":"additional","affiliation":[{"name":"Department of Osteology and BiomechanicsUniversity Medical Center Hamburg-EppendorfHamburgGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rene","family":"Santer","sequence":"additional","affiliation":[{"name":"Department of PediatricsUniversity Medical Center Hamburg-EppendorfHamburgGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chayarop","family":"Supanchart","sequence":"additional","affiliation":[{"name":"Institute of Medical GeneticsCharite University Medical CenterBerlinGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe","family":"Kornak","sequence":"additional","affiliation":[{"name":"Institute of Medical GeneticsCharite University Medical CenterBerlinGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea Del","family":"Fattore","sequence":"additional","affiliation":[{"name":"Ospedale Pediatrico Bambino Ges\u00f9Regenerative Medicine UnitRomeItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J","family":"Jentsch","sequence":"additional","affiliation":[{"name":"Physiology and Pathology of Ion TransportLeibniz-Institut f\u00fcr Molekulare Pharmakologie (FMP) and Max-Delbr\u00fcck-Centrum f\u00fcr Molekulare Medizin (MDC)BerlinGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Teti","sequence":"additional","affiliation":[{"name":"Department of Biotechnological and Applied SciencesUniversity of L'AquilaL'AquilaItaly"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ansgar","family":"Schulz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent MedicineUniversity Medical Center UlmUlmGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten","family":"Schinke","sequence":"additional","affiliation":[{"name":"Department of Osteology and BiomechanicsUniversity Medical Center Hamburg-EppendorfHamburgGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Amling","sequence":"additional","affiliation":[{"name":"Department of Osteology and BiomechanicsUniversity Medical Center Hamburg-EppendorfHamburgGermany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2013,9,23]]},"reference":[{"key":"2024020318550475300_jbmr2100-bib-0001","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.bone.2007.08.029","article-title":"Genetics, pathogenesis and complications of osteopetrosis","volume":"42","author":"Del 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infancy","volume":"49","author":"Aker","year":"2012","journal-title":"J Med Genet."},{"key":"2024020318550475300_jbmr2100-bib-0005","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1093\/hmg\/10.17.1767","article-title":"The mutational spectrum of human malignant autosomal recessive osteopetrosis","volume":"10","author":"Sobacchi","year":"2001","journal-title":"Hum Mol Genet."},{"key":"2024020318550475300_jbmr2100-bib-0006","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/77131","article-title":"Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis","volume":"25","author":"Frattini","year":"2000","journal-title":"Nat Genet."},{"key":"2024020318550475300_jbmr2100-bib-0007","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1093\/hmg\/9.13.2059","article-title":"Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant 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Lancet."},{"key":"2024020318550475300_jbmr2100-bib-0021","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1007\/s00198-012-2011-0","article-title":"Impaired bone mineralization accompanied by low vitamin D and secondary hyperparathyroidism in patients with femoral neck fracture","volume":"24","author":"Seitz","year":"2013","journal-title":"Osteoporos Int."},{"key":"2024020318550475300_jbmr2100-bib-0022","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/jbmr.1805","article-title":"Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee","volume":"28","author":"Dempster","year":"2013","journal-title":"J Bone Miner Res."},{"key":"2024020318550475300_jbmr2100-bib-0023","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.bone.2012.11.009","article-title":"Osteopetrosis, osteopetrorickets and hypophosphatemic rickets differentially affect dentin and enamel mineralization","volume":"53","author":"Koehne","year":"2013","journal-title":"Bone."},{"key":"2024020318550475300_jbmr2100-bib-0024","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1148\/radiol.2302020388","article-title":"The rugger jersey spine sign","volume":"230","author":"Wittenberg","year":"2004","journal-title":"Radiology."},{"key":"2024020318550475300_jbmr2100-bib-0025","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/415287a","article-title":"X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity","volume":"415","author":"Dutzler","year":"2002","journal-title":"Nature."},{"key":"2024020318550475300_jbmr2100-bib-0026","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1007\/s00439-002-0861-9","article-title":"Chloride channel 7 (CLCN7) gene mutations in intermediate autosomal recessive osteopetrosis","volume":"112","author":"Campos-Xavier","year":"2003","journal-title":"Hum Genet."},{"key":"2024020318550475300_jbmr2100-bib-0027","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/0896-6273(95)90050-0","article-title":"George AL Jr. An aspartic acid residue important for voltage-dependent gating of human muscle chloride channels","volume":"15","author":"Fahlke","year":"1995","journal-title":"Neuron."},{"key":"2024020318550475300_jbmr2100-bib-0028","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1093\/hmg\/3.7.1123","article-title":"Proof of a non-functional muscle chloride channel in recessive myotonia congenita (Becker) by detection of a 4 base pair deletion","volume":"3","author":"Heine","year":"1994","journal-title":"Hum Mol Genet."},{"key":"2024020318550475300_jbmr2100-bib-0029","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s00439-008-0583-8","article-title":"Advances in osteoclast biology resulting from the study of osteopetrotic mutations","volume":"124","author":"Segovia-Silvestre","year":"2009","journal-title":"Hum Genet."},{"key":"2024020318550475300_jbmr2100-bib-0030","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S8756-3282(99)00257-4","article-title":"Normative data for iliac bone histomorphometry in growing children","volume":"26","author":"Glorieux","year":"2000","journal-title":"Bone."},{"key":"2024020318550475300_jbmr2100-bib-0031","doi-asserted-by":"crossref","first-page":"384","DOI":"10.2106\/00004623-198062030-00008","article-title":"Human osteopetrosis: a histological, ultrastructural, and biochemical study","volume":"62","author":"Shapiro","year":"1980","journal-title":"J Bone Joint Surg Am."},{"key":"2024020318550475300_jbmr2100-bib-0032","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/0221-8747(81)90033-3","article-title":"Induction of bone resorption by parathyroid hormone in congenital malignant osteopetrosis","volume":"3","author":"Glorieux","year":"1981","journal-title":"Metab Bone Dis Relat Res."},{"key":"2024020318550475300_jbmr2100-bib-0033","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/8756-3282(91)90030-M","article-title":"Morphologic features of bone in human osteopetrosis","volume":"12","author":"Helfrich","year":"1991","journal-title":"Bone."},{"key":"2024020318550475300_jbmr2100-bib-0034","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.bone.2007.10.021","article-title":"Bone mineralization density distribution in health and disease","volume":"42","author":"Roschger","year":"2008","journal-title":"Bone."},{"key":"2024020318550475300_jbmr2100-bib-0035","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1097\/00003086-199309000-00008","article-title":"Osteopetrorickets. The paradox of plenty. Pathophysiology and treatment","volume":"294","author":"Kaplan","year":"1993","journal-title":"Clin Orthop Relat Res."},{"key":"2024020318550475300_jbmr2100-bib-0036","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1515\/jpem.2010.149","article-title":"Scarcity despite wealth: osteopetrorickets","volume":"23","author":"Demirel","year":"2010","journal-title":"J Pediatr Endocrinol Metab."},{"key":"2024020318550475300_jbmr2100-bib-0037","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/S0016-5085(97)90000-7","article-title":"Abnormal gastric histology and decreased acid production in cholecystokinin-B\/gastrin receptor-deficient mice","volume":"112","author":"Langhans","year":"1997","journal-title":"Gastroenterology."},{"key":"2024020318550475300_jbmr2100-bib-0038","doi-asserted-by":"crossref","first-page":"e12585","DOI":"10.1371\/journal.pone.0012585","article-title":"The G215R mutation in the Cl\u2212\/H+-antiporter ClC-7 found in ADO II osteopetrosis does not abolish function but causes a severe trafficking defect","volume":"5","author":"Schulz","year":"2010","journal-title":"PLoS One."},{"key":"2024020318550475300_jbmr2100-bib-0039","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1085\/jgp.110.2.165","article-title":"Inward rectification in ClC-0 chloride channels caused by mutations in several protein regions","volume":"110","author":"Ludewig","year":"1997","journal-title":"J Gen Physiol."},{"key":"2024020318550475300_jbmr2100-bib-0040","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/bonekey.2012.46","volume":"1","author":"Teti","year":"2012","journal-title":"Bonekey Rep."},{"key":"2024020318550475300_jbmr2100-bib-0041","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1038\/ng2076","article-title":"Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL","volume":"39","author":"Sobacchi","year":"2007","journal-title":"Nat Genet."},{"key":"2024020318550475300_jbmr2100-bib-0042","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1359\/jbmr.080907","article-title":"Paget's disease of bone: histologic analysis of 754 patients","volume":"24","author":"Seitz","year":"2009","journal-title":"J Bone Miner Res."},{"key":"2024020318550475300_jbmr2100-bib-0043","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1111\/j.1875-595X.2004.tb00298.x","article-title":"Recalcitrant osteomyelitis following tooth extraction in a case of malignant osteopetrosis","volume":"54","author":"Batra","year":"2004","journal-title":"Int Dent J."},{"key":"2024020318550475300_jbmr2100-bib-0044","doi-asserted-by":"crossref","first-page":"77","DOI":"10.17796\/jcpd.27.1.2q4w7l0p73r54l27","article-title":"Infantile osteopetrosis: a case report with osteomyelitis of the maxilla","volume":"27","author":"Toranzo Fernandez","year":"2002","journal-title":"J Clin Pediatr Dent."},{"key":"2024020318550475300_jbmr2100-bib-0045","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.tripleo.2009.02.015","article-title":"Osteomyelitis of the mandible secondary to infantile osteopetrosis: a case report","volume":"107","author":"Yamada","year":"2009","journal-title":"Oral Surg Oral Med Oral Pathol Oral Radiol Endod."},{"key":"2024020318550475300_jbmr2100-bib-0046","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/nrendo.2013.137","article-title":"Osteopetrosis: genetics, treatment and new insights into osteoclast function","volume":"9","author":"Sobacchi","year":"2013","journal-title":"Nat Rev Endocrinol."}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.2100","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/29\/4\/982\/56566493\/jbmr2100.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/29\/4\/982\/56566493\/jbmr2100.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:50:47Z","timestamp":1710341447000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/29\/4\/982-991\/7599044"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,9,23]]},"references-count":46,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2013,9,23]]},"published-print":{"date-parts":[[2014,4,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.2100","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2014,4,1]]},"published":{"date-parts":[[2013,9,23]]}}}