A Novel Splice Mutation in PLS3 Causes X-linked Early Onset Low-Turnover Osteoporosis

Abstract

Genetic factors play an important role in the development of osteoporosis. Several monogenic forms of osteoporosis have been recognized, most recently an X-chromosomal form resulting from mutations in the gene encoding plastin 3 (PLS3). PLS3 is a protein involved in actin bundle formation in the cytoskeleton. We present a large family with early onset osteoporosis and X-linked inheritance. Phenotyping was performed on 19 family members and whole-exome sequencing on 7 family members (5 with a diagnosis of early onset osteoporosis and 2 with normal bone parameters). Osteoporosis had its onset in childhood and was characterized by recurrent peripheral fractures, low bone mineral density (BMD), vertebral compression fractures, and significant height loss in adulthood. Males were in general more severely affected than females. Bone histomorphometry findings in 4 males and 1 female showed severe trabecular osteoporosis, low amount of osteoid, and decreased mineral apposition rate, indicating impaired bone formation; resorption parameters were increased in some. All affected subjects shared a single base substitution (c.73-24T > A) in intron 2 of PLS3 on Xq23. The mutation, confirmed by Sanger sequencing, segregated according to the skeletal phenotype. The mutation introduces a new acceptor splice site with a predicted splice score of 0.99 and, thereby, as confirmed by cDNA sequencing, induces the insertion of 22 bases between exons 2 and 3, causing a frameshift and premature termination of mRNA translation (p.Asp25Alafs à 17). The mutation affects the first N-terminal calcium-binding EF-hand domain and abolishes all calcium-and actin-binding domains of the protein. Our results confirm the role of PLS3 mutations in early onset osteoporosis. The mechanism whereby PLS3 affects bone health is unclear, but it may be linked to osteocyte dendrite function and skeletal mechanosensing. Future studies are needed to elucidate the role of PLS3 in osteoporosis and to define optimal treatment.

New Genetic Forms of Childhood-Onset Primary Osteoporosis

“…The authors evaluated transiliac bone biopsies from 2 of them and saw evidence of low osteoid maturation time, suggesting that Plastin 3 could be involved in the mineralization process. The authors also described a low amount of trabecular bone but with a normal lamellation pattern, which is in accordance with what Laine et al [41] reported from bone biopsies of 5 patients with PLS3 mutations.…”

“…Extraskeletal features that are often associated with OI such as blue sclerae, discolored teeth, joint hyperlaxity or short stature, are usually absent. To date, only 8 families with childhood-onset primary osteoporosis due to PLS3 mutations have been described, and the majority of the severely affected individuals are males [36,40,41]. Due to its location on the X chromosome, males have only one copy of PLS3 , which explains why males can present with a more severe phenotype than females.…”

“…Biochemical measurements of affected patients have shown normal serum calcium and phosphate levels, urinary bone turnover markers within the normal range and no evidence of hypercalciuria [40,41]. Extraskeletal features that are often associated with OI such as blue sclerae, discolored teeth, joint hyperlaxity or short stature, are usually absent.…”

Rare copy number variants in array-based comparative genomic hybridization in early-onset skeletal fragility

“…On the other hand, SNVs and deletions in PLS3 have already been reported in patients with osteoporosis (39)(40)(41)(42)(43). Recently, some patients with PLS3 deletions have been described, and apart from severe osteoporosis there is a bone mineralization defect (42).…”

Genetics of osteoporosis: searching for candidate genes for bone fragility

“…Further reports have supported a causative role for PLS3 mutations in the genesis of X-linked osteoporosis (48,49). While the biological role of PLS3 in bone is still largely unknown, a disturbance in osteocyte mechanosensing has been proposed as a putative mechanism based on animal model observations (16).…”