{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T22:56:05Z","timestamp":1782773765536,"version":"3.54.5"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2006,7,1]],"date-time":"2006-07-01T00:00:00Z","timestamp":1151712000000},"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":[[2006,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We report three novel osteopetrosis patients with OSTM1 mutations and review two that have been previously described. Our analysis suggests that OSTM1 defines a new subset of patients with severe central nervous system involvement. This defect is also present in the gl mouse, which could represent a good model to study the role of the gene in the pathogenesis of this disease.<\/jats:p>\n               <jats:p>Introduction: Autosomal recessive osteopetrosis (ARO) is a severe hereditary bone disease whose cellular basis is in the osteoclast, but with heterogeneous molecular defects. In addition to the TCIRG1 and the ClCN7 genes, whose mutations account for \u223c55% and 10% of cases, respectively, the OSTM1 gene has been described thus far in only two ARO patients.<\/jats:p>\n               <jats:p>Materials and Methods: We report here three novel ARO patients presenting with severe primary central nervous system involvement in addition to the classical stigmata of severe bone sclerosis, growth failure, anemia, thrombocytopenia, and visual impairment with optic atrophy. In addition we analyzed the brain morphology and histology of the grey lethal mutant mouse.<\/jats:p>\n               <jats:p>Results: The analysis of the OSTM1 gene in two patients, both from Kuwait, showed homozygous two nucleotide deletion in exon 2, leading to a frameshift and premature termination. The third (Lebanese) patient showed a single point mutation in exon 1, leading to a nonsense mutation. The clinical neurological evaluation of the two Kuwaiti patients by CT and MRI scans showed a defect in the white matter, with a specific diagnosis of severe cerebral atrophy. The gl brain showed a diffuse translucent appearance with loss of the normal demarcation between the white and the grey matter, features consistent with myelin loss or hypomyelination. Histological and myelin staining analysis evidenced an atrophy of the corpus callosum with loss of myelin fibers, and in cortical areas, loss of the normal lamination consistent with multiple foci of cortical dysplasia.<\/jats:p>\n               <jats:p>Conclusions: These findings suggest that OSTM1-dependent ARO defines a new subset of patients with severe central nervous system involvement leading to a very poor prognosis. The fact that central nervous system involvement is also present in the gl mouse mutant suggests that this mouse is a good model to test possible therapies.<\/jats:p>","DOI":"10.1359\/jbmr.060403","type":"journal-article","created":{"date-parts":[[2006,7,4]],"date-time":"2006-07-04T05:47:20Z","timestamp":1151992040000},"page":"1098-1105","source":"Crossref","is-referenced-by-count":100,"title":["Mutations in <i>OSTM1<\/i> (Grey Lethal) Define a Particularly Severe Form of Autosomal Recessive Osteopetrosis With Neural Involvement"],"prefix":"10.1093","volume":"21","author":[{"given":"Alessandra","family":"Pangrazio","sequence":"first","affiliation":[{"name":"Institute for Biomedical Technologies, CNR, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro Luigi","family":"Poliani","sequence":"additional","affiliation":[{"name":"Department of Pathology I, University of Brescia, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Megarbane","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de G\u00e9n\u00e9tique M\u00e9dicale, Campus des Sciences M\u00e9dicales, Beyrouth, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e9rard","family":"Lefranc","sequence":"additional","affiliation":[{"name":"Laboratoire d'Immunog\u00e9n\u00e9tique Mol\u00e9culaire, Universit\u00e9 Montpellier II, Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Lanino","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology-Oncology - BMT Unit, Gaslini Institute, Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja","family":"Di Rocco","sequence":"additional","affiliation":[{"name":"Unit of Rare Diseases, Gaslini Institute, Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Rucci","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Technologies, CNR, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Lucchini","sequence":"additional","affiliation":[{"name":"Biotechnologies Research Center, Catholic University of Sacro Cuore, Cremona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Ravanini","sequence":"additional","affiliation":[{"name":"Department of Pathology I, University of Brescia, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Facchetti","sequence":"additional","affiliation":[{"name":"Department of Pathology I, University of Brescia, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Abinun","sequence":"additional","affiliation":[{"name":"Children's BMT Unit, Newcastle General Hospital, Newcastle upon Tyne, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Vezzoni","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Technologies, CNR, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Villa","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Technologies, CNR, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Frattini","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Technologies, CNR, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024013019383596600_bib1","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1002\/humu.20076","article-title":"TCIRG1-dependent recessive osteopetrosis: Mutation analysis, functional identification of the splicing defects and in vitro rescue by U1snRNA","volume":"24","author":"Susani","year":"2004","journal-title":"Hum Mutat"},{"key":"2024013019383596600_bib2","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/humu.10165","article-title":"Novel mutations in the TCIRG1 gene encoding the a3 subunit of the vacuolar proton pump in patients affected by infantile malignant osteopetrosis","volume":"21","author":"Scimeca","year":"2003","journal-title":"Hum Mutat"},{"key":"2024013019383596600_bib3","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0002-9440(10)63798-4","article-title":"Genotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis","volume":"162","author":"Taranta","year":"2003","journal-title":"Am J Pathol"},{"key":"2024013019383596600_bib4","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":"2024013019383596600_bib5","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1038\/77131","article-title":"Defects in the 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":"2024013019383596600_bib6","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 osteopetrosis","volume":"9","author":"Kornak","year":"2000","journal-title":"Hum Mol Genet"},{"key":"2024013019383596600_bib7","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1359\/jbmr.2003.18.10.1740","article-title":"Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis","volume":"18","author":"Frattini","year":"2003","journal-title":"J Bone Miner Res"},{"key":"2024013019383596600_bib8","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0092-8674(01)00206-9","article-title":"Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man","volume":"104","author":"Kornak","year":"2001","journal-title":"Cell"},{"key":"2024013019383596600_bib9","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1093\/hmg\/10.25.2861","article-title":"Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene","volume":"10","author":"Cleiren","year":"2001","journal-title":"Hum Mol Genet"},{"key":"2024013019383596600_bib10","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/nature03720","article-title":"Chloride\/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5","volume":"436","author":"Picollo","year":"2005","journal-title":"Nature"},{"key":"2024013019383596600_bib11","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/nature03860","article-title":"Voltage-dependent electrogenic chloride\/proton exchange by endosomal CLC proteins","volume":"436","author":"Scheel","year":"2005","journal-title":"Nature"},{"key":"2024013019383596600_bib12","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1359\/JBMR.040407","article-title":"Severe malignant osteopetrosis caused by a GL gene mutation","volume":"19","author":"Quarello","year":"2004","journal-title":"J Bone Miner Res"},{"key":"2024013019383596600_bib13","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1002\/humu.20028","article-title":"Identification of a novel mutation in the coding region of the grey-lethal gene OSTM1 in human malignant infantile osteopetrosis","volume":"23","author":"Ramirez","year":"2004","journal-title":"Hum Mutat"},{"key":"2024013019383596600_bib14","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nm842","article-title":"Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human","volume":"9","author":"Chalhoub","year":"2003","journal-title":"Nat Med"},{"key":"2024013019383596600_bib15","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/sj.bmt.1704194","article-title":"Long-term outcome of haematopoietic stem cell transplantation in autosomal recessive osteopetrosis: An EBMT report","volume":"32","author":"Driessen","year":"2003","journal-title":"Bone Marrow Transplant"},{"key":"2024013019383596600_bib16","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1016\/S0022-3476(05)82004-9","article-title":"Bone marrow transplantation for autosomal recessive osteopetrosis. A report from the Working Party on Inborn Errors of the European Bone Marrow Transplantation Group","volume":"125","author":"Gerritsen","year":"1994","journal-title":"J Pediatr"},{"key":"2024013019383596600_bib17","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1038\/sj.emboj.7600576","article-title":"Loss of the chloride channel ClC-7 leads to lysosomal storage disease and neurodegeneration","volume":"24","author":"Kasper","year":"2005","journal-title":"EMBO J"},{"key":"2024013019383596600_bib18","doi-asserted-by":"crossref","first-page":"8270","DOI":"10.1073\/pnas.1432965100","article-title":"Promotion of G alpha i3 subunit down-regulation by GIPN, a putative E3 ubiquitin ligase that interacts with RGS-GAIP","volume":"100","author":"Fischer","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024013019383596600_bib19","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1136\/adc.80.3.273","article-title":"Importance of neurological assessment before bone marrow transplantation for osteopetrosis","volume":"80","author":"Abinun","year":"1999","journal-title":"Arch Dis Child"},{"key":"2024013019383596600_bib20","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1136\/jmg.2005.036673","article-title":"Clinical, genetic and cellular analysis of forty-nine osteopetrotic patients: Implications for diagnosis and treatment","volume":"43","author":"Del Fattore","year":"2006","journal-title":"J Med Genet"},{"key":"2024013019383596600_bib21","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1007\/s00223-002-1087-5","article-title":"Type II benign osteopetrosis (Albers-Schonberg disease) caused by a novel mutation in CLCN7 presenting with unusual clinical manifestations","volume":"74","author":"Letizia","year":"2004","journal-title":"Calcif Tissue Int"},{"key":"2024013019383596600_bib22","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":"2024013019383596600_bib23","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1359\/jbmr.2003.18.8.1513","article-title":"Chloride channel (ClCN7) gene mutations and autosomal dominant osteopetrosis, type II","volume":"18","author":"Waguespack","year":"2003","journal-title":"J Bone Miner Res"},{"key":"2024013019383596600_bib24","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/ajmg.a.30490","article-title":"Intrafamilial phenotypic variability of osteopetrosis due to chloride channel 7 (CLCN7) mutations","volume":"133","author":"Campos-Xavier","year":"2005","journal-title":"Am J Med Genet"},{"key":"2024013019383596600_bib25","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1046\/j.1365-2990.2003.00474.x","article-title":"Neurological aspects of osteopetrosis","volume":"29","author":"Steward","year":"2003","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2024013019383596600_bib26","first-page":"528","article-title":"Association of severe autosomal recessive osteopepetrosis and Dandy-Walker syndrome with agenesis of the corpus callosum","volume":"67","author":"Ben Hamouda","year":"2001","journal-title":"Acta Orthop Belg"},{"key":"2024013019383596600_bib27","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1159\/000120923","article-title":"Association of infantile neuroaxonal dystrophy and osteopetrosis: A rare autosomal recessive disorder","volume":"22","author":"Rees","year":"1995","journal-title":"Pediatr Neurosurg"},{"key":"2024013019383596600_bib28","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1007\/BF00293320","article-title":"Lectin histochemistry of infantile lysosomal storage disease associated with osteopetrosis","volume":"87","author":"Alroy","year":"1994","journal-title":"Acta Neuropathol (Berl)"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1359%2Fjbmr.060403","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/21\/7\/1098\/56478593\/5650210713.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/21\/7\/1098\/56478593\/5650210713.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:46:40Z","timestamp":1710341200000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/21\/7\/1098-1105\/7593187"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,7,1]]},"references-count":28,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2009,12,4]]},"published-print":{"date-parts":[[2006,7,1]]}},"URL":"https:\/\/doi.org\/10.1359\/jbmr.060403","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2006,7,1]]},"published":{"date-parts":[[2006,7,1]]}}}