Identification of biallelicLRRK1mutations in osteosclerotic metaphyseal dysplasia and evidence for locus heterogeneity

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.

Leucine-rich repeat kinase-1 regulates osteoclast function by modulating RAC1/Cdc42 Small GTPase phosphorylation and activation

“…In addition, Lrrk1 KO mice responded normally to PTH anabolic treatments but were resistant to ovariectomy-induced bone loss. Consistent with our observations in the Lrrk1 KO mouse model, our recent human genetic studies have identified a severe osteopetrosis phenotype at the vertebra and the metaphysis of long and short tubular bones in a patient with Lrrk1 deletion and frame-shifted mutation (15). These observations make Lrrk1 an attractive antiresorptive drug target because Lrrk1 KO mice have normal membranous bone, and inhibiting Lrrk1 may not interfere with osteoclast-coupled bone formation in the maxilla and mandible or cause osteonecrosis of the jaw.…”

“…Previous findings of the dramatic reduction in bone resorption and the persistent resistance to ovariectomy-induced bone loss in the Lrrk1 KO mice (36) and the recent identification of an osteosclerotic patient with an autosomal recessive mutation of Lrrk1 (15) provide unequivocal evidence that Lrrk1 plays a critical role in regulation of bone homeostasis. Mice with disruption of Lrrk1 exhibited severe osteopetrosis phenotypes in the femurs, tibias, and vertebrae due to dysfunction of mature osteoclasts.…”

“…This patient suffered from an osteosclerotic metaphyseal dysplasia, a unique form of osteopetrosis characterized by severe osteosclerosis localized to the metaphyses of the long and short tubular bones. The vertebral bodies and pelvis showed marginal sclerosis while the patient's skull seemed normal, as measured by X-ray radiography (15). The modest skull and mandible phenotypes of Lrrk1 KO mice and the patient with Lrrk1 mutation compared with the phenotypes of long bones and vertebrae are consistent with evidence that regulation of osteoclast function is different in intramembranous vs. endochondral bone.…”

LRRK1 regulation of actin assembly in osteoclasts involves serine 5 phosphorylation of L‐plastin

“…Lrrk1 KO mice have normal teeth, are healthy through one year of age and respond to anabolic PTH treatment, but are resistant to ovariectomy-induced bone loss (9) . More recently, mutations in LRRK1 gene have been identified in human patients (10) . The clinical features of affected patients resulting from the dysfunction of Lrrk1 in OC were very similar to the skeletal phenotypes observed in the Lrrk1 KO mice (9,10) .…”

“…More recently, mutations in LRRK1 gene have been identified in human patients (10) . The clinical features of affected patients resulting from the dysfunction of Lrrk1 in OC were very similar to the skeletal phenotypes observed in the Lrrk1 KO mice (9,10) . These studies suggest that Lrrk1 could be an antagonist drug target for treatment of osteoporosis.…”