Identification of a novel LRRK1 mutation in a family with osteosclerotic metaphyseal dysplasia

J Hum Genet. 2017 Mar;62(3):437-441. doi: 10.1038/jhg.2016.136. Epub 2016 Nov 10.


Osteosclerotic metaphyseal dysplasia (OSMD) is a rare skeletal dysplasia characterized by osteosclerotic metaphyses with osteopenic diaphyses of the long tubular bones. Our previous study identified a homozygous elongation mutation in leucine-rich repeat kinase 1 gene (LRRK1) in a patient with OSMD and showed that Lrrk1 knockout mice exhibited phenotypic similarity with OSMD. Here we report a second LRRK1 mutation in Indian sibs with OSMD. They had homozygous mutation (c.5971_5972insG) that produces an elongated mutant protein (p.A1991Gfs*31) similar to the first case. The sibs had normal stature, normal intelligence and recurrent fractures. The common radiographic feature was asymmetric and variable sclerosis of vertebral end plates, pelvic margin and metaphyses of tubular bones. One of the sibs had facial dysmorphisms, dentine abnormalities and acro-osteolysis. A comparison between the three OSMD cases with LRRK1 mutations with different ages suggested that the sclerotic lesions resolved with age. Our findings further support that LRRK1 would cause a subset of OSMD cases.

MeSH terms

  • Acro-Osteolysis / diagnosis
  • Acro-Osteolysis / genetics*
  • Acro-Osteolysis / pathology
  • Adolescent
  • Adult
  • Female
  • Fractures, Bone / diagnosis
  • Fractures, Bone / genetics*
  • Fractures, Bone / pathology
  • Gene Expression
  • Homozygote
  • Humans
  • India
  • Male
  • Mutation*
  • Osteochondrodysplasias / diagnosis
  • Osteochondrodysplasias / genetics*
  • Osteochondrodysplasias / pathology
  • Osteosclerosis / diagnosis
  • Osteosclerosis / genetics*
  • Osteosclerosis / pathology
  • Protein Serine-Threonine Kinases / genetics*
  • Recurrence
  • Siblings
  • Spine / metabolism
  • Spine / pathology


  • LRRK1 protein, human
  • Protein Serine-Threonine Kinases

Supplementary concepts

  • Pyle disease