Aritoshi Iida1, Weirong Xing2, Martine K F Docx3, Tomoki Nakashima4, Zheng Wang5, Mamori Kimizuka6, Wim Van Hul7, Dietz Rating8, Jürgen Spranger9, Hirohumi Ohashi10, Noriko Miyake11, Naomichi Matsumoto11, Subburaman Mohan2, Gen Nishimura12, Geert Mortier7, Shiro Ikegawa13. 1. Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan. 2. Musculoskeletal Disease Center, Jerry L Pettis Memorial VA Medical Center, Loma Linda, California, USA Department of Medicine, Loma Linda University, Loma Linda, California, USA. 3. Department of Paediatric Chronic Diseases and Nephrology, Queen Paola Children's Hospital, Antwerp, Belgium. 4. Department of Cell Signaling, Graduate school of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan Japan Science and Technology Agency, PRESTO, Tokyo, Japan. 5. Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan State Key Laboratory of Medical Molecular Biology, McKusick-Zhang Center for Genetic Medicine and Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. 6. Department of Orthopaedics, National Rehabilitation Center for Disabled Children, Tokyo, Japan. 7. Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium. 8. Department of Pediatrics, St Annastiftskinderkrankenhaus, Ludwigshafen, Germany. 9. Centre for Pediatrics and Adolescent Medicine, Freiburg, Germany. 10. Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan. 11. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. 12. Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Fuchu, Japan. 13. Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan Department of Orthopaedics, National Rehabilitation Center for Disabled Children, Tokyo, Japan.
Abstract
BACKGROUND: 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. OBJECTIVE: To identify the disease gene for OSMD. METHODS AND RESULTS: By whole exome sequencing in a boy with OSMD, we identified a homozygous 7 bp deletion (c.5938_5944delGAGTGGT) in the LRRK1 gene. His skeletal phenotype recapitulated that seen in the Lrrk1-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 Lrrk1-deficient mice showed that the deletion was a loss of function mutation. Genetic analysis of LRRK1 in two unrelated patients with OSMD suggested that OSMD is a genetically heterogeneous condition. CONCLUSIONS: This is the first study to identify the causative gene of OSMD. Our study provides evidence that LRRK1 plays a critical role in the regulation of bone mass in humans. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
BACKGROUND: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. OBJECTIVE: To identify the disease gene for OSMD. METHODS AND RESULTS: By whole exome sequencing in a boy with OSMD, we identified a homozygous 7 bp deletion (c.5938_5944delGAGTGGT) in the LRRK1 gene. His skeletal phenotype recapitulated that seen in the Lrrk1-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 Lrrk1-deficient mice showed that the deletion was a loss of function mutation. Genetic analysis of LRRK1 in two unrelated patients with OSMD suggested that OSMD is a genetically heterogeneous condition. CONCLUSIONS: This is the first study to identify the causative gene of OSMD. Our study provides evidence that LRRK1 plays a critical role in the regulation of bone mass in humans. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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