Identification of bi-allelicLRRK1mutations inosteosclerotic metaphyseal dysplasiaand evidence for locus heterogeneity

Osteosclerotic metaphyseal dysplasia is a unique form of osteopetrosis characterized by dysplasiaof metaphyses of tubular bones with increased bone density. By exome sequencing, we found a homozygous mutation, c.5938_5944del[p.E1980Afs*66]in LRRK1 (Leucin-rich repeat kinase 1). LRRK1 was highly expressed in differentiated osteoclast. The patient’s phenotype was very similar to that of Lrrk1 knockout mice that we previously reported. In vitro transfection rescue experiments using osteoclasts from the knockout mice showed that the deletion caused a loss of bone-resorbing function of osteoclast. LRRK1 can be afascinating new drug target ofosteoporosis, like RANKL and sclerostin. (By Dr. Aritoshi Iida, http://jmg.bmj.com/content/early/2016/04/07/jmedgenet-2016-103756 )