{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:42:55Z","timestamp":1790142175804,"version":"4.0.1"},"reference-count":30,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T00:00:00Z","timestamp":1558310400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,5,20]],"date-time":"2019-05-20T00:00:00Z","timestamp":1558310400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT\u2010148508"],"award-info":[{"award-number":["PJT\u2010148508"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Cellular Biochemistry"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Autosomal recessive osteopetrosis (ARO) is a severe genetic bone disease characterized by high bone density due to mutations that affect formation or function of osteoclasts. Mutations in the\n                    <jats:italic>a<\/jats:italic>\n                    3 subunit of the vacuolar\u2010type H\n                    <jats:sup>+<\/jats:sup>\n                    \u2010ATPase (encoded by T\u2010cell immune regulator 1 [\n                    <jats:italic>TCIRG1<\/jats:italic>\n                    ]) are responsible for ~50% of all ARO cases. We identified a novel\n                    <jats:italic>TCIRG1<\/jats:italic>\n                    (c.G630A) mutation responsible for an unusually mild form of the disease. To characterize this mutation, osteoclasts were differentiated using peripheral blood monocytes from the patient (c.G630A\/c.G630A), male sibling (+\/+), unaffected female sibling (+\/c.G630A), and unaffected parent (+\/c.G630A). Osteoclast formation, bone\u2010resorbing function, TCIRG1 protein, and mRNA expression levels were assessed. The c.G630A mutation did not affect osteoclast differentiation; however, bone\u2010resorbing function was decreased. Both TCIRG1 protein and full\u2010length\n                    <jats:italic>TCIRG1<\/jats:italic>\n                    mRNA expression levels were also diminished in the affected patient's sample. The c.G630A mutation replaces the last nucleotide of exon 6 and may cause splicing defects. We analyzed the\n                    <jats:italic>TCIRG1<\/jats:italic>\n                    splicing pattern between exons 4 to 8 and detected deletions of exons 5, 6, 7, and 5\u20106 (\u0394E56). These deletions were only observed in c.G630A\/c.G630A and +\/c.G630A samples, but not in +\/+ controls. Among these deletions, only \u0394E56 maintained the reading frame and was predicted to generate an 85\u2009kDa protein. Exons 5\u20106 encode an uncharacterized portion of the cytoplasmic N\u2010terminal domain of\n                    <jats:italic>a<\/jats:italic>\n                    3, a domain not involved in proton translocation. To investigate the effect of \u0394E56 on V\u2010ATPase function, we transformed yeast with plasmids carrying full\u2010length or truncated Vph1p, the yeast ortholog of\n                    <jats:italic>a<\/jats:italic>\n                    3. Both proteins were expressed; however, \u0394E56\u2010Vph1p transformed yeast failed to grow on Zn\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010containing plates, a growth assay dependent on V\u2010ATPase\u2010mediated vacuolar acidification. In conclusion, our results show that the \u0394E56 truncated protein is not functional, suggesting that the mild ARO phenotype observed in the patient is likely due to the residual full\u2010length protein expression.\n                  <\/jats:p>","DOI":"10.1002\/jcb.28979","type":"journal-article","created":{"date-parts":[[2019,5,21]],"date-time":"2019-05-21T00:32:04Z","timestamp":1558398724000},"page":"17180-17193","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Novel c.G630A\n                    <i>TCIRG1<\/i>\n                    mutation causes aberrant splicing resulting in an unusually mild form of autosomal recessive osteopetrosis"],"prefix":"10.1002","volume":"120","author":[{"given":"Ralph A.","family":"Zirngibl","sequence":"first","affiliation":[{"name":"Faculty of Dentistry University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Wang","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeqi","family":"Yao","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morris F.","family":"Manolson","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Krueger","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology and Blood and Marrow Transplant The Hospital for Sick Children  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Dupuis","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Department of Paediatrics The Hospital for Sick Children, University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Mendoza\u2010Londono","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Department of Paediatrics The Hospital for Sick Children, University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2369-3324","authenticated-orcid":false,"given":"Irina","family":"Voronov","sequence":"additional","affiliation":[{"name":"Faculty of Dentistry University of Toronto  Toronto Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,5,20]]},"reference":[{"key":"e_1_2_9_1_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2013.137"},{"key":"e_1_2_9_1_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20101172\u20104\u20105"},{"key":"e_1_2_9_1_4_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.063032"},{"key":"e_1_2_9_1_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2272"},{"key":"e_1_2_9_1_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M309914200"},{"key":"e_1_2_9_1_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M302436200"},{"key":"e_1_2_9_1_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u20101\u201061779\u2010415\u20105_11"},{"key":"e_1_2_9_1_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2005.04.028"},{"key":"e_1_2_9_1_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2203"},{"key":"e_1_2_9_1_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.24489"},{"key":"e_1_2_9_1_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)36755-8"},{"key":"e_1_2_9_1_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2011.07.014"},{"key":"e_1_2_9_1_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.053"},{"key":"e_1_2_9_1_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20084"},{"key":"e_1_2_9_1_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006394"},{"key":"e_1_2_9_1_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2005.03.065"},{"key":"e_1_2_9_1_18_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1999.5751"},{"key":"e_1_2_9_1_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.25574"},{"key":"e_1_2_9_1_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12881\u2010017\u20100506\u20104"},{"key":"e_1_2_9_1_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00198\u2010011\u20101878\u20105"},{"key":"e_1_2_9_1_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20076"},{"key":"e_1_2_9_1_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00223\u2010008\u20109196\u20104"},{"key":"e_1_2_9_1_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00774\u2010010\u20100228\u20106"},{"key":"e_1_2_9_1_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/77131"},{"key":"e_1_2_9_1_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2517"},{"key":"e_1_2_9_1_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2017.108"},{"key":"e_1_2_9_1_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u2010981\u201010\u20107757\u20109_14"},{"key":"e_1_2_9_1_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2017.02.002"},{"key":"e_1_2_9_1_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2018.02.031"},{"key":"e_1_2_9_1_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw533"}],"container-title":["Journal 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