A novel frameshift deletion in PLS3 causing severe primary osteoporosis

Costantini, Alice; Krallis, Panagiotis; Kämpe, Anders; Karavitakis, Emmanouil; Taylan, Fulya; Mäkitie, Outi; Doulgeraki, Artemis

doi:10.1038/s10038-018-0472-5

Cited by 20 publications

(18 citation statements)

References 16 publications

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“…In summary, most of the osteoporosis-related PLS3 variants are frameshift [108,122,135,137,138,144] or nonsense mutations resulting in premature termination codons [108,128,130,140], which are followed by mRNA decay [108,128,131,135]. Next to that, partial deletions within PLS3 were identified [126,140,146].…”

Section: Osteoporosismentioning

confidence: 99%

Plastin 3 in health and disease: a matter of balance

Wolff

Strathmann

Müller

et al. 2021

Cell. Mol. Life Sci.

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For a long time, PLS3 (plastin 3, also known as T-plastin or fimbrin) has been considered a rather inconspicuous protein, involved in F-actin-binding and -bundling. However, in recent years, a plethora of discoveries have turned PLS3 into a highly interesting protein involved in many cellular processes, signaling pathways, and diseases. PLS3 is localized on the X-chromosome, but shows sex-specific, inter-individual and tissue-specific expression variability pointing towards skewed X-inactivation. PLS3 is expressed in all solid tissues but usually not in hematopoietic cells. When escaping X-inactivation, PLS3 triggers a plethora of different types of cancers. Elevated PLS3 levels are considered a prognostic biomarker for cancer and refractory response to therapies. When it is knocked out or mutated in humans and mice, it causes osteoporosis with bone fractures; it is the only protein involved in actin dynamics responsible for osteoporosis. Instead, when PLS3 is upregulated, it acts as a highly protective SMN-independent modifier in spinal muscular atrophy (SMA). Here, it seems to counteract reduced F-actin levels by restoring impaired endocytosis and disturbed calcium homeostasis caused by reduced SMN levels. In contrast, an upregulation of PLS3 on wild-type level might cause osteoarthritis. This emphasizes that the amount of PLS3 in our cells must be precisely balanced; both too much and too little can be detrimental. Actin-dynamics, regulated by PLS3 among others, are crucial in a lot of cellular processes including endocytosis, cell migration, axonal growth, neurotransmission, translation, and others. Also, PLS3 levels influence the infection with different bacteria, mycosis, and other pathogens.

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Section: Osteoporosismentioning

confidence: 99%

Plastin 3 in health and disease: a matter of balance

Wolff

Strathmann

Müller

et al. 2021

Cell. Mol. Life Sci.

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“…These differentially expressed genes between PU groups were associated with bone metabolism or immune responses. For instance, mutations of the gene encoding plastin-3 (PLS3) were associated with severe primary osteoporosis [32,33] and shown to affect bone mineral homeostasis through regulation of osteoclast activity [34]. CST7 was upregulated by the induction of Runx2, an osteoblast master transcription factor, in C4-2B cells [35].…”

Section: Discussionmentioning

confidence: 99%

Identification of the Key Molecular Drivers of Phosphorus Utilization Based on Host miRNA-mRNA and Gut Microbiome Interactions

Ponsuksili

Reyer

Hadlich

et al. 2020

IJMS

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Phosphorus is an essential mineral for all living organisms and a limited resource worldwide. Variation and heritability of phosphorus utilization (PU) traits were observed, indicating the general possibility of improvement. Molecular mechanisms of PU, including host and microbial effects, are still poorly understood. The most promising molecules that interact between the microbiome and host are microRNAs. Japanese quail representing extremes for PU were selected from an F2 population for miRNA profiling of the ileal tissue and subsequent association with mRNA and microbial data of the same animals. Sixty-nine differentially expressed miRNAs were found, including 21 novel and 48 known miRNAs. Combining miRNAs and mRNAs based on correlated expression and target prediction revealed enrichment of transcripts in functional pathways involved in phosphate or bone metabolism such as RAN, estrogen receptor and Wnt signaling, and immune pathways. Out of 55 genera of microbiota, seven were found to be differentially abundant between PU groups. The study reveals molecular interactions occurring in the gut of quail which represent extremes for PU including miRNA-16-5p, miR-142b-5p, miR-148a-3p, CTDSP1, SMAD3, IGSF10, Bacteroides, and Alistipes as key indicators due to their trait-dependent differential expression and occurrence as hub-members of the network of molecular drivers of PU.

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“…The gene's X-chromosomal location explained why PLS3 mutations affected mainly hemizygous males while the heterozygous females did not present significant bone fragility. Since the original description, several other families and single patients have been reported [81][82][83][84][85][86][87][88][89]. Based on these, it is evident, that PLS3 mutations cause in affected males severe, early-onset and progressive osteoporosis predominated by multiple spinal compression fractures.…”

Section: X-chromosomal Osteoporosis Due To Pls3 Mutationsmentioning

confidence: 99%

Early-Onset Osteoporosis

Mäkitie

Zillikens

2021

Calcif Tissue Int

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Osteoporosis is a skeletal disorder with enhanced bone fragility, usually affecting the elderly. It is very rare in children and young adults and the definition is not only based on a low BMD (a Z-score < − 2.0 in growing children and a Z-score ≤ − 2.0 or a T-score ≤ − 2.5 in young adults) but also on the occurrence of fragility fractures and/or the existence of underlying chronic diseases or secondary factors such as use of glucocorticoids. In the absence of a known chronic disease, fragility fractures and low BMD should prompt extensive screening for secondary causes, which can be found in up to 90% of cases. When fragility fractures occur in childhood or young adulthood without an evident secondary cause, investigations should explore the possibility of an underlying monogenetic bone disease, where bone fragility is caused by a single variant in a gene that has a major role in the skeleton. Several monogenic forms relate to type I collagen, but other forms also exist. Loss-of-function variants in LRP5 and WNT1 may lead to early-onset osteoporosis. The X-chromosomal osteoporosis caused by PLS3 gene mutations affects especially males. Another recently discovered form relates to disturbed sphingolipid metabolism due to SGMS2 mutations, underscoring the complexity of molecular pathology in monogenic early-onset osteoporosis. Management of young patients consists of treatment of secondary factors, optimizing lifestyle factors including calcium and vitamin D and physical exercise. Treatment with bone-active medication should be discussed on a personalized basis, considering the severity of osteoporosis and underlying disease versus the absence of evidence on anti-fracture efficacy and potential harmful effects in pregnancy.

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A novel frameshift deletion in PLS3 causing severe primary osteoporosis

Cited by 20 publications

References 16 publications

Plastin 3 in health and disease: a matter of balance

Plastin 3 in health and disease: a matter of balance

Identification of the Key Molecular Drivers of Phosphorus Utilization Based on Host miRNA-mRNA and Gut Microbiome Interactions

Early-Onset Osteoporosis

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