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

Schwebach, Christopher L.; Kudryashova, Elena; Kudryashov, Dmitri S.

doi:10.3389/fcell.2020.635783

Cited by 9 publications

(15 citation statements)

References 77 publications

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“…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 ].…”

Section: Discussionmentioning

confidence: 99%

“…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 ].…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

“…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 ].…”

Section: Introductionmentioning

confidence: 99%

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

Brlek

Antičević

Molnar³

et al. 2021

Genes

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Osteogenesis imperfecta (OI) represents a complex spectrum of genetic bone diseases that occur primarily due to mutations and deletions of the COL1A1 and COL1A2 genes. Recent molecular studies of the network of signaling pathways have contributed to a better understanding of bone remodeling and the pathogenesis of OI caused by mutations in many other genes associated with normal bone mineralization. In this paper, a case of a rare X-linked variant of OI with a change in the gene encoding plastin 3—a protein important for the regulation of the actin cytoskeleton, is presented. A 16-year-old patient developed ten bone fractures caused by minor trauma or injury, including a compression fracture of the second lumbar vertebra during his lifetime. Next-generation sequencing analysis did not show pathologically relevant deviations in the COL1A1 and COL1A2 genes. Targeted gene analyses (Skeletal disorder panel) of the patient, his father, mother and sister were then performed, detecting variants of uncertain significance (VUS) for genes PLS3, FN1 and COL11A2. A variant in the PLS3 gene were identified in the patient, his mother and sister. Since the PLS3 gene is located on the X chromosome, the mother and sister showed no signs of the disease. Although the variant in the PLS3 gene (c.685G>A (p.Gly229Arg)) has not yet been described in the literature, nor is its pathogenicity known, clinical findings combined with genetic testing showed that this variant may explain the cause of X-linked OI in our patient. This rare case of the PLS3 variant of X-linked OI might point to a novel target for personalized therapy in patients with this severe disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Brlek

Antičević

Molnar³

et al. 2021

Genes

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“…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 .…”

Section: Introductionmentioning

confidence: 99%

Allosteric Regulation of Human Plastins

Schwebach

Kudryashova

Agrawal

et al. 2021

Preprint

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Plastins/fimbrins are conserved actin-bundling proteins contributing to motility, cytokinesis, and other cellular processes by organizing actin assemblies of strikingly different geometries as in aligned bundles and branched networks. We propose that this unique ability stems from an allosteric communication between plastins’ two actin-binding domains (ABD1/2) engaged in a tight spatial association. We found that although ABD1 binds actin first, ABD2 can bind to actin three orders of magnitude stronger if not inhibited by an equally strong allosteric engagement with ABD1. Binding of ABD1 to actin lessened the inhibition, enabling weak bundling within aligned bundles. A mutation mimicking physiologically relevant phosphorylation at the ABD1-ABD2 interface strongly reduced their association, dramatically potentiating actin cross-linking. Cryo-EM reconstruction revealed the ABD1-actin interface and enabled modeling of the plastin bridge to confirm domain separation in parallel bundles. The characteristic domain organization with a strong allosteric inhibition imposed by ABD1 on ABD2 allows plastins to tune cross-linking, contributing to the assembly and remodeling of actin assemblies with different morphological and functional properties defining the unique place of plastins in actin organization.

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Early-Onset Osteoporosis: Rare Monogenic Forms Elucidate the Complexity of Disease Pathogenesis Beyond Type I Collagen

Costantini

Mäkitie

Hartmann

et al. 2020

Journal of Bone and Mineral Research

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Early-onset osteoporosis (EOOP), characterized by low bone mineral density (BMD) and fractures, affects children, premenopausal women and men aged <50 years. EOOP may be secondary to a chronic illness, long-term medication, nutritional deficiencies, etc. If no such cause is identified, EOOP is regarded primary and may then be related to rare variants in genes playing a pivotal role in bone homeostasis. If the cause remains unknown, EOOP is considered idiopathic. The scope of this review is to guide through clinical and genetic diagnostics of EOOP, summarize the present knowledge on rare monogenic forms of EOOP, and describe how analysis of bone biopsy samples can lead to a better understanding of the disease pathogenesis. The diagnostic pathway of EOOP is often complicated and extensive assessments may be needed to reliably exclude secondary causes. Due to the genetic heterogeneity and overlapping features in the various genetic forms of EOOP and other bone fragility disorders, the genetic diagnosis usually requires the use of next-generation sequencing to investigate several genes simultaneously. Recent discoveries have elucidated the complexity of disease pathogenesis both regarding genetic architecture and bone tissue-level pathology. Two rare monogenic forms of EOOP are due to defects in genes partaking in the canonical WNT pathway: LRP5 and WNT1. Variants in the genes encoding plastin-3 (PLS3) and sphingomyelin synthase 2 (SGMS2) have also been found in children and young adults with skeletal fragility. The molecular mechanisms leading from gene defects to clinical manifestations are often not fully understood. Detailed analysis of patient-derived transiliac bone biopsies gives valuable information to understand disease pathogenesis, distinguishes EOOP from other bone fragility disorders, and guides in patient management, but is not widely available in clinical settings. Despite the great advances in this field, EOOP remains an insufficiently explored entity and further research is needed to optimize diagnostic and therapeutic approaches.

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

Cited by 9 publications

References 77 publications

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

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

Allosteric Regulation of Human Plastins

Early-Onset Osteoporosis: Rare Monogenic Forms Elucidate the Complexity of Disease Pathogenesis Beyond Type I Collagen

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