Identification of biallelic LRRK1 mutations in osteosclerotic metaphyseal dysplasia and evidence for locus heterogeneity.
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.
['Iida|Aritoshi|A|', 'Xing|Weirong|W|', 'Docx|Martine K F|MK|', 'Nakashima|Tomoki|T|', 'Wang|Zheng|Z|', 'Kimizuka|Mamori|M|', 'Van Hul|Wim|W|', 'Rating|Dietz|D|', 'Spranger|Jürgen|J|', 'Ohashi|Hirohumi|H|', 'Miyake|Noriko|N|', 'Matsumoto|Naomichi|N|', 'Mohan|Subburaman|S|', 'Nishimura|Gen|G|', 'Mortier|Geert|G|', 'Ikegawa|Shiro|S|']
D000818:Animals D001842:Bone and Bones D002675:Child, Preschool D006720:Homozygote D006801:Humans D008297:Male D051379:Mice D009154:Mutation D010009:Osteochondrodysplasias D010010:Osteoclasts D010022:Osteopetrosis D010026:Osteosclerosis D017346:Protein Serine-Threonine Kinases
LRRK1 mutation Osteosclerotic metaphyseal dysplasia Whole exome sequencing Lrrk1 deficient mouse