Osteoporosis Caused by Mutations in PLS3: Clinical and Bone Tissue Characteristics

Abstract

Mutations in PLS3 have been identified as a cause of bone fragility in children, but the bone phenotype associated with PLS3 mutations has not been reported in detail. PLS3 is located on the X chromosome and encodes the actin-binding protein plastin 3. Here we describe skeletal findings in 4 boys from 2 families with mutations in PLS3 (c.994_995delGA; p.Asp332 Ã in family 1; c.1433T > C; p. Leu478Pro in family 2). When first evaluated between 4 and 8 years of age, these boys had a history of one to four long-bone fractures. Mild vertebral compression fractures were identified in each boy. No obvious extraskeletal disease manifestations were present. Lumbar spine areal bone mineral density (LS-aBMD) Z-scores ranged from -1.7 to -3.5, but height was normal. Iliac bone histomorphometry in 2 patients showed low trabecular bone volume and a low osteoid maturation time but normal bone formation rate and osteoclast surface. Quantitative backscattered electron imaging (qBEI) did not reveal a major abnormality in bone mineralization density distribution. The 2 boys from family 1 received oral alendronate for 6 years, which normalized LS-aBMD. The mothers of the 4 boys did not have a history of fractures and had normal LS-aBMD. However, one of these mothers had low bone mass at the distal radius, as measured by peripheral quantitative computed tomography (pQCT). In conclusion, hemizygous mutations in PLS3 are associated with osteoporosis and bone fragility in childhood, but in contrast to bone fragility caused by mutations in collagen type I encoding genes, there is no hypermineralization of mineralized bone matrix.

New Genetic Forms of Childhood-Onset Primary Osteoporosis

“…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.…”

“…However, there are other suggestions for the function of Plastin 3 in the skeleton as well. Fahiminiya et al [40] studied 4 boys with PLS3 mutations and childhood-onset 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.…”

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).…”