title: Identification of biallelic LRRK1 mutations in osteosclerotic metaphyseal dysplasia and evidence for locus heterogeneity.
abstract: 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.
  
  
  
  To identify the disease gene for OSMD.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
authors.forename: Aritoshi
authors.initials: A
authors.lastname: Iida
authors.affiliation: Musculoskeletal Disease Center, Jerry L Pettis Memorial VA Medical Center, Loma Linda, California, USA Department of Medicine, Loma Linda University, Loma Linda, California, USA.
authors.forename: Weirong
authors.initials: W
authors.lastname: Xing
authors.affiliation: Department of Paediatric Chronic Diseases and Nephrology, Queen Paola Children's Hospital, Antwerp, Belgium.
authors.forename: Martine K F
authors.initials: MK
authors.lastname: Docx
authors.affiliation: 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.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nakashima
authors.affiliation: 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.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, National Rehabilitation Center for Disabled Children, Tokyo, Japan.
authors.forename: Mamori
authors.initials: M
authors.lastname: Kimizuka
authors.affiliation: Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Van Hul
authors.affiliation: Department of Pediatrics, St Annastiftskinderkrankenhaus, Ludwigshafen, Germany.
authors.forename: Dietz
authors.initials: D
authors.lastname: Rating
authors.affiliation: Centre for Pediatrics and Adolescent Medicine, Freiburg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Spranger
authors.affiliation: Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan.
authors.forename: Hirohumi
authors.initials: H
authors.lastname: Ohashi
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Musculoskeletal Disease Center, Jerry L Pettis Memorial VA Medical Center, Loma Linda, California, USA Department of Medicine, Loma Linda University, Loma Linda, California, USA.
authors.forename: Subburaman
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Fuchu, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.affiliation: Department of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Mortier
authors.affiliation: 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.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ikegawa
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000473:pathology; D002675:Child, Preschool; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000235:genetics*; D010010:Osteoclasts / Q000473:pathology; D010022:Osteopetrosis / Q000235:genetics; D010026:Osteosclerosis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: C510751:LRRK1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: LRRK1 mutation; Lrrk1 deficient mouse; Osteosclerotic metaphyseal dysplasia; Whole exome sequencing