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Original article
Identification of biallelic LRRK1 mutations in osteosclerotic metaphyseal dysplasia and evidence for locus heterogeneity
  1. Aritoshi Iida1,
  2. Weirong Xing2,3,
  3. Martine K F Docx4,
  4. Tomoki Nakashima5,6,
  5. Zheng Wang1,7,
  6. Mamori Kimizuka8,
  7. Wim Van Hul9,
  8. Dietz Rating10,
  9. Jürgen Spranger11,
  10. Hirohumi Ohashi12,
  11. Noriko Miyake13,
  12. Naomichi Matsumoto13,
  13. Subburaman Mohan2,3,
  14. Gen Nishimura14,
  15. Geert Mortier9,
  16. Shiro Ikegawa1,8
  1. 1Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan
  2. 2Musculoskeletal Disease Center, Jerry L Pettis Memorial VA Medical Center, Loma Linda, California, USA
  3. 3Department of Medicine, Loma Linda University, Loma Linda, California, USA
  4. 4Department of Paediatric Chronic Diseases and Nephrology, Queen Paola Children's Hospital, Antwerp, Belgium
  5. 5Department of Cell Signaling, Graduate school of Medical and Dental Science, Tokyo Medical and Dental University, Tokyo, Japan
  6. 6Japan Science and Technology Agency, PRESTO, Tokyo, Japan
  7. 7State 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
  8. 8Department of Orthopaedics, National Rehabilitation Center for Disabled Children, Tokyo, Japan
  9. 9Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium
  10. 10Department of Pediatrics, St Annastiftskinderkrankenhaus, Ludwigshafen, Germany
  11. 11Centre for Pediatrics and Adolescent Medicine, Freiburg, Germany
  12. 12Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan
  13. 13Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  14. 14Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Fuchu, Japan
  1. Correspondence to Professor Shiro Ikegawa, Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan; sikegawa{at} or Professor Geert Mortier, Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem 2650, Belgium; geert.mortier{at}


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.

  • Osteosclerotic metaphyseal dysplasia
  • Whole exome sequencing
  • LRRK1 mutation
  • Lrrk1 deficient mouse

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