ECTS Abstracts (2015) 1 P239

PLS3 Gene Variation in Childhood Fractures and Primary Osteoporosis

Anders J Kämpe1, Riikka E Mäkitie2, Nina Jäntti1,3, Minna Pekkinen2, Giedre Grigelioniene1,3 & Outi Mäkitie1,2

1Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden, 2Folkhälsan Institute of Genetics and University of Helsinki, Helsinki, Finland, 3Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Mutations in the gene PLS3 have recently been found as being a cause of early-onset primary osteoporosis. This type of osteoporosis affects males more often and more severely than females, because PLS3 is located on the X-chromosome. The encoded protein Plastin3 functions as an actin bundling protein and is abundantly expressed in solid tissue. PLS3 is highly expressed in osteocytic dendrites and is likely to have a role in skeletal mechanosensing. The aim of this study is to explore the question of how prevalent PLS3 mutations are in childhood-onset primary osteoporosis. Altogether 32 patients with childhood-onset primary osteoporosis, without a molecular diagnosis, were included. The diagnosis of primary osteoporosis was based on low BMD with a history of recurrent, low impact, peripheral fractures or vertebral compression fractures and exclusion of secondary osteoporosis. Using PCR and Sanger sequencing techniques, all coding exons and exon-intron boundaries of the PLS3 gene were sequenced for all the 32 patients. A previously not described nonsense mutation in exon 8, c.766C>T; p.Arg256X, was found in a presently 28-year-old male, with a history of multiple vertebral compression fractures since early childhood and a markedly low BMD. He also has slightly blue sclerae and joint hyperlaxity. The PLS3 mutation was inherited from his mother, who has osteopenia and joint hyperlaxity. Based on cDNA analysis the mutation results in synthesis of a truncated protein as mutated RNA escapes nonsense-mediated RNA decay. Several PLS3 variants were found in the remaining patients but none of these variants were regarded as disease-causing. In conclusion, PLS3 mutations explain some cases of early-onset osteoporosis but our results do not support first-line screening of PLS3 in patients with childhood-onset primary osteoporosis. The pathogenetic mechanisms through which PLS3 mutations lead to the phenotypic manifestations need to be explored in future studies.

Disclosure: This work was supported by the Swedish Research Council (2013-2603).

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