Plastin 3 in X-Linked Osteoporosis: Imbalance of Ca2+-Dependent Regulation Is Equivalent to Protein Loss

Abstract

Osteogenesis imperfecta is a genetic disorder disrupting bone development and remodeling. The primary causes of osteogenesis imperfecta are pathogenic variants of collagen and collagen processing genes. However, recently variants of the actin bundling protein plastin 3 have been identified as another source of osteogenesis imperfecta. Plastin 3 is a highly conserved protein involved in several important cellular structures and processes and is controlled by intracellular Ca2+ which potently inhibits its actin-bundling activity. The precise mechanisms by which plastin 3 causes osteogenesis imperfecta remain unclear, but recent advances have contributed to our understanding of bone development and the actin cytoskeleton. Here, we review the link between plastin 3 and osteogenesis imperfecta highlighting in vitro studies and emphasizing the importance of Ca2+ regulation in the localization and functionality of plastin 3.

X-Linked Osteogenesis Imperfecta Possibly Caused by a Novel Variant in PLS3

“…Different variants in PLS3 , which is ubiquitously expressed in solid tissues, lead to decreased bone mineral density [ 22 ]. Previous findings suggest that the majority of the OI-linked PLS3 pathogenic variants are either loss-of-function changes (nonsense or frameshift varaints) which rarely result in translated protein products due to nonsense-mediated mRNA decay [ 16 , 23 ]. Separately, a rare single nucleotide polymorphism of the PLS3 gene was reported in association with osteoporosis in postmenopausal women [ 24 ].…”

“…Different variants in PLS3 have shown differences in distribution between lamellipodia and focal adhesions [ 16 ]. Studies on the chicken homolog of the PLS3 gene have shown that the function of its protein product can be linked to mechanosensitivity of osteocytes [ 26 ].…”

“…The clinical presentation in hemizygous men matched the presentation of classical OI and was variable in heterozygous women [ 14 ]. The main role of PLS3 is in F-actin-binding, which consequently suggests that PLS3 participates in all processes dependent on F-actin dynamics, such as cell motility, cell division, focal adhesion, endocytosis, neurotransmission, vesicle trafficking, axonal local translation, and intracellular calcium PLS3-dependent processes [ 15 , 16 ]. Plastins are proteins with a single polypeptide chain composed of two tandem repeats of actin-binding domains (ABD1 and ABD2).…”

“…Each ABD is assembled from two tandem calponin-homology (CH) domains (CH1 and CH2 in ABD1, and CH3 and CH4 in ABD2) [ 17 ]. The binding of each ABD to two separate actin filaments promotes the formation of a bundle resulting in distinct F-actin organization [ 16 ].…”

Allosteric Regulation of Human Plastins

“…Mutations in PLS3 lead to severe X-linked hereditary osteoporosis with bone fragility [25][26][27][28][29][30][31][32][33][34][35] . Congenital osteoporosis develops upon deletion and truncations in PLS3 gene (reviewed in 36 ), but also due to point mutations resulting in PLS3 variants, which either lose the ability to bundle F-actin or display perturbed sensitivity to Ca 2+ 37 . By contributing to endocytosis 38 and migration, PLS3 plays neuroprotective roles by lessening the toxicity of pathogenic poly-glutamine-containing proteins 39 , alleviating symptoms of spinal muscular atrophy 40,41 , and coordinating neuronal cell migration in embryogenesis 42 .…”