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Autosomal-dominant osteopetrosis type II (ADOII) is most often caused by mutation of the\n                    <jats:italic>CLCN7<\/jats:italic>\n                    gene leading to impaired bone resorption. Autosomal recessive osteopetrosis (ARO) is a more severe form and is frequently accompanied by additional morbidities. We report an adult male presenting with classical clinical and radiological features of ADOII. Genetic analyses showed no amino-acid-converting mutation in\n                    <jats:italic>CLCN7<\/jats:italic>\n                    but an apparent haploinsufficiency and suppression of\n                    <jats:italic>CLCN7<\/jats:italic>\n                    mRNA levels in peripheral blood mononuclear cells. Next generation sequencing revealed low-frequency intronic homozygous variations in\n                    <jats:italic>CLCN7<\/jats:italic>\n                    , suggesting recessive inheritance. In silico analysis of an intronic duplication c.595-120_595-86dup revealed additional binding sites for Serine- and Arginine-rich Splicing Factors (SRSF), which is predicted to impair\n                    <jats:italic>CLCN7<\/jats:italic>\n                    expression. Quantitative backscattered electron imaging and histomorphometric analyses revealed bone tissue and material abnormalities. Giant osteoclasts were present and additionally to lamellar bone, and abundant woven bone and mineralized cartilage were observed, together with increased frequency and thickness of cement lines. Bone mineralization density distribution (BMDD) analysis revealed markedly increased average mineral content of the dense bone (CaMean\n                    <jats:italic>T<\/jats:italic>\n                    -score\u2009+\u200910.1) and frequency of bone with highest mineral content (CaHigh\n                    <jats:italic>T<\/jats:italic>\n                    -score\u2009+\u200919.6), suggesting continued mineral accumulation and lack of bone remodelling. Osteocyte lacunae sections (OLS) characteristics were unremarkable except for an unusually circular shape. Together, our findings suggest that the reduced expression of\n                    <jats:italic>CLCN7<\/jats:italic>\n                    mRNA in osteoclasts, and possibly also osteocytes, causes poorly remodelled bone with abnormal bone matrix with high mineral content. This together with the lack of adequate bone repair mechanisms makes the material brittle and prone to fracture. While the skeletal phenotype and medical history were suggestive of ADOII, genetic analysis revealed that this is a possible mild case of ARO due to deep intronic mutation.\n                  <\/jats:p>","DOI":"10.1007\/s00223-022-00988-8","type":"journal-article","created":{"date-parts":[[2022,5,26]],"date-time":"2022-05-26T15:02:56Z","timestamp":1653577376000},"page":"430-444","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Mild Case of Autosomal Recessive Osteopetrosis Masquerading as the Dominant Form Involving Homozygous Deep Intronic Variations in the CLCN7 Gene"],"prefix":"10.1007","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7741-7187","authenticated-orcid":false,"given":"Jochen G.","family":"Hofstaetter","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3123-9861","authenticated-orcid":false,"given":"Gerald J.","family":"Atkins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9178-7846","authenticated-orcid":false,"given":"Hajime","family":"Kato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-6825","authenticated-orcid":false,"given":"Masakazu","family":"Kogawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6575-8443","authenticated-orcid":false,"given":"St\u00e9phane","family":"Blouin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9923-4920","authenticated-orcid":false,"given":"Barbara M.","family":"Misof","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Roschger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8321-9806","authenticated-orcid":false,"given":"Andreas","family":"Evdokiou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongqing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucian B.","family":"Solomon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Findlay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4071-5372","authenticated-orcid":false,"given":"Nobuaki","family":"Ito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,5,26]]},"reference":[{"key":"988_CR1","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1148\/rg.317115093","volume":"31","author":"LL Ihde","year":"2011","unstructured":"Ihde LL, Forrester DM, Gottsegen CJ, Masih S, Patel DB, Vachon LA, White EA, Matcuk GR Jr (2011) Sclerosing bone dysplasias: review and differentiation from other causes of osteosclerosis. 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Hofstaetter, Gerald J. Atkins, Hajime Kato, Masakazu Kogawa, St\u00e9phane Blouin, Barbara M. Misof, Paul Roschger, Andreas Evdokiou, Dongqing Yang, Lucian B. Solomon, David M. Findlay, and Nobuaki Ito have no disclosures of conflicts of interest to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Research ethics approval for the study was obtained from the Royal Adelaide Hospital Human Research Ethics Committee (Approval No. RAH130114) and informed consent to both conduct the study and publish the findings was obtained from the proband. No animals were used in this study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights and Informed Consent"}}]}}