{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T22:45:47Z","timestamp":1787697947464,"version":"build-2784847793"},"reference-count":23,"publisher":"BMJ","issue":"8","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2016,3,19]]},"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Osteosclerotic metaphyseal dysplasia (OSMD) is a unique form of osteopetrosis characterised by severe osteosclerosis localised to the bone ends. The mode of inheritance is autosomal recessive. Its genetic basis is not known.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To identify the disease gene for OSMD.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>By whole exome sequencing in a boy with OSMD, we identified a homozygous 7\u2005bp deletion (c.5938_5944delGAGTGGT) in the <jats:italic>LRRK1<\/jats:italic> gene. His skeletal phenotype recapitulated that seen in the <jats:italic>Lrrk1<\/jats:italic>-deficient mouse. The shared skeletal hallmarks included severe sclerosis in the undermodelled metaphyses and epiphyseal margins of the tubular bones, costal ends, vertebral endplates and margins of the flat bones. The deletion is predicted to result in an elongated LRRK1 protein (p.E1980Afs*66) that lacks a part of its WD40 domains. In vitro functional studies using osteoclasts from <jats:italic>Lrrk1<\/jats:italic>-deficient mice showed that the deletion was a loss of function mutation. Genetic analysis of <jats:italic>LRRK1<\/jats:italic> in two unrelated patients with OSMD suggested that OSMD is a genetically heterogeneous condition.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This is the first study to identify the causative gene of OSMD. Our study provides evidence that <jats:italic>LRRK1<\/jats:italic> plays a critical role in the regulation of bone mass in humans.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmedgenet-2016-103756","type":"journal-article","created":{"date-parts":[[2016,4,8]],"date-time":"2016-04-08T13:35:45Z","timestamp":1460122545000},"page":"568-574","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":50,"title":["Identification of biallelic <i>LRRK1<\/i> mutations in osteosclerotic metaphyseal dysplasia and evidence for locus heterogeneity"],"prefix":"10.1136","volume":"53","author":[{"given":"Aritoshi","family":"Iida","sequence":"first","affiliation":[{"name":"Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weirong","family":"Xing","sequence":"additional","affiliation":[{"name":"Musculoskeletal Disease Center, Jerry L Pettis Memorial VA Medical Center, Loma Linda, California, USA"},{"name":"Department of Medicine, Loma Linda University, Loma Linda, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine K F","family":"Docx","sequence":"additional","affiliation":[{"name":"Department of Paediatric Chronic Diseases and Nephrology, Queen Paola Children's Hospital, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Nakashima","sequence":"additional","affiliation":[{"name":"Department of Cell Signaling, Graduate school of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan"},{"name":"Japan Science and Technology Agency, PRESTO, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan"},{"name":"State Key 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