{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T22:10:56Z","timestamp":1772662256575,"version":"3.50.1"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T00:00:00Z","timestamp":1706918400000},"content-version":"vor","delay-in-days":3637,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,7,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Mutations in the TCIRG1 gene, coding for a subunit of the osteoclast proton pump, are responsible for more than 50% of cases of human malignant autosomal recessive osteopetrosis (ARO), a rare inherited bone disease with increased bone density owing to a failure in bone resorption. A wide variety of mutations has been described, including missense, nonsense, small deletions\/insertions, splice-site mutations, and large genomic deletions, all leading to a similar severe presentation. So far, to the best of our knowledge, no report of a mild phenotype owing to recessive TCIRG1 mutations is present neither in our series of more than 100 TCIRG1-dependent ARO patients nor in the literature. Here we describe an 8-year-old patient referred to us with a clinical diagnosis of ARO, based on radiological findings; of note, no neurological or hematological defects were present in this girl. Surprisingly, we identified a novel nucleotide change in intron 15 of the TCIRG1 gene at the homozygous state, leading to the production of multiple aberrant transcripts, but also, more importantly, of a limited amount of the normal transcript. Our results show that a low level of normal TCIRG1 protein can dampen the clinical presentation of TCIRG1-dependent ARO. On this basis, a small amount of protein might be sufficient to rescue, at least partially, the severe ARO phenotype, and this is particularly important when gene therapy approaches are considered. In addition, we would also recommend that the TCIRG1 gene be included in the molecular diagnosis of mild forms of human ARO. \u00a9 2014 Italian National Research Council. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2203","type":"journal-article","created":{"date-parts":[[2014,2,18]],"date-time":"2014-02-18T12:47:51Z","timestamp":1392727671000},"page":"1646-1650","source":"Crossref","is-referenced-by-count":23,"title":["As Little as Needed: The Extraordinary Case of a Mild Recessive Osteopetrosis Owing to a Novel Splicing Hypomorphic Mutation in the <i>TCIRG1<\/i> Gene"],"prefix":"10.1093","volume":"29","author":[{"given":"Cristina","family":"Sobacchi","sequence":"first","affiliation":[{"name":"Humanitas Clinical and Research CenterRozzanoItaly"},{"name":"Unit\u00e1 Operativa di Supporto (UOS)\/Institute of Genetic and Biomedical Research (IRGB)Milan Unit, National Research Council (CNR)MilanItaly"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandra","family":"Pangrazio","sequence":"additional","affiliation":[{"name":"Humanitas Clinical and Research CenterRozzanoItaly"},{"name":"Unit\u00e1 Operativa di Supporto (UOS)\/Institute of Genetic and Biomedical Research (IRGB)Milan Unit, National Research Council (CNR)MilanItaly"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio Gonz\u00e1lez-Meneses","family":"Lopez","sequence":"additional","affiliation":[{"name":"Unidad de Dismorfologia, Servicio de PediatriaHospital Universitario Virgen del RocioSevillaSpain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego Pascual-Vaca","family":"Gomez","sequence":"additional","affiliation":[{"name":"Department of PathologyHospital Universitario Virgen del Roc\u00edoSevillaSpain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Elena","family":"Caldana","sequence":"additional","affiliation":[{"name":"Humanitas Clinical and Research CenterRozzanoItaly"},{"name":"Unit\u00e1 Operativa di Supporto (UOS)\/Institute of Genetic and Biomedical Research (IRGB)Milan Unit, National Research Council (CNR)MilanItaly"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Susani","sequence":"additional","affiliation":[{"name":"Humanitas Clinical and Research CenterRozzanoItaly"},{"name":"Unit\u00e1 Operativa di Supporto (UOS)\/Institute of Genetic and Biomedical Research (IRGB)Milan Unit, National Research Council (CNR)MilanItaly"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Vezzoni","sequence":"additional","affiliation":[{"name":"Humanitas Clinical and Research CenterRozzanoItaly"},{"name":"Unit\u00e1 Operativa di Supporto (UOS)\/Institute of Genetic and Biomedical Research (IRGB)Milan Unit, National Research Council (CNR)MilanItaly"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Villa","sequence":"additional","affiliation":[{"name":"Humanitas Clinical and Research CenterRozzanoItaly"},{"name":"Unit\u00e1 Operativa di Supporto (UOS)\/Institute of Genetic and Biomedical Research (IRGB)Milan Unit, National Research Council (CNR)MilanItaly"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2014,2,18]]},"reference":[{"key":"2024020318514228900_jbmr2203-bib-0001","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."},{"key":"2024020318514228900_jbmr2203-bib-0002","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":"2024020318514228900_jbmr2203-bib-0003","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":"2024020318514228900_jbmr2203-bib-0004","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/S8756-3282(01)00684-6","article-title":"Novel mutations in the a3 subunit of vacuolar H(+)-adenosine triphosphatase in a Japanese patient with infantile malignant osteopetrosis","volume":"30","author":"Michigami","year":"2002","journal-title":"Bone."},{"key":"2024020318514228900_jbmr2203-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":"2024020318514228900_jbmr2203-bib-0006","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":"2024020318514228900_jbmr2203-bib-0007","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":"2024020318514228900_jbmr2203-bib-0008","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1002\/humu.20076","article-title":"TCIRG1-dependent recessive 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infantile malignant osteopetrosis","volume":"131","author":"Phadke","year":"2010","journal-title":"Indian J Med Res."},{"key":"2024020318514228900_jbmr2203-bib-0012","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s00774-010-0228-6","article-title":"Novel mutation of TCIRG1 and clinical pictures of two infantile malignant osteopetrosis patients","volume":"29","author":"Yuan","year":"2011","journal-title":"J Bone Miner Metab."},{"key":"2024020318514228900_jbmr2203-bib-0013","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1007\/s00198-011-1878-5","article-title":"Autosomal recessive osteopetrosis: report of 41 novel mutations in the TCIRG1 gene and diagnostic implications","volume":"23","author":"Pangrazio","year":"2012","journal-title":"Osteoporos Int."},{"key":"2024020318514228900_jbmr2203-bib-0014","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1359\/jbmr.2003.18.10.1740","article-title":"Chloride channel ClCN7 mutations are responsible for 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