Plastin 3 in health and disease: a matter of balance

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

Evaluation of potential effects of Plastin 3 overexpression and low-dose SMN-antisense oligonucleotides on putative biomarkers in spinal muscular atrophy mice.

OBJECTIVES:Spinal muscular atrophy (SMA) is a devastating motor neuron disorder caused by homozygous loss of the survival motor neuron 1 (SMN1) gene and insufficient functional SMN protein produced by the SMN2 copy gene. Additional genetic protective modifiers such as Plastin 3 (PLS3) can counteract SMA pathology despite insufficient SMN protein. Recently, Spinraza, an SMN antisense oligonucleotide (ASO) that restores full-length SMN2 transcripts, has been FDA- and EMA-approved for SMA therapy. Hence, the availability of biomarkers allowing a reliable monitoring of disease and therapy progression would be of great importance. Our objectives were (i) to analyse the feasibility of SMN and of six SMA biomarkers identified by the BforSMA study in the Taiwanese SMA mouse model, (ii) to analyse the effect of PLS3 overexpression on these biomarkers, and (iii) to assess the impact of low-dose SMN-ASO therapy on the level of SMN and the six biomarkers. METHODS:At P10 and P21, the level of SMN and six putative biomarkers were compared among SMA, heterozygous and wild type mice, with or without PLS3 overexpression, and with or without presymptomatic low-dose SMN-ASO subcutaneous injection. SMN levels were measured in whole blood by ECL immunoassay and of six SMA putative biomarkers, namely Cartilage Oligomeric Matrix Protein (COMP), Dipeptidyl Peptidase 4 (DPP4), Tetranectin (C-type Lectin Family 3 Member B, CLEC3B), Osteopontin (Secreted Phosphoprotein 1, SPP1), Vitronectin (VTN) and Fetuin A (Alpha 2-HS Glycoprotein, AHSG) in plasma. RESULTS:SMN levels were significantly discernible between SMA, heterozygous and wild type mice. However, no significant differences were measured upon low-dose SMN-ASO treatment compared to untreated animals. Of the six biomarkers, only COMP and DPP4 showed high and SPP1 moderate correlation with the SMA phenotype. PLS3 overexpression neither influenced the SMN level nor the six biomarkers, supporting the hypothesis that PLS3 acts as an independent protective modifier

Adverse perinatal outcomes in gestational diabetes mellitus with and without SARS-CoV-2 infection during pregnancy: results from two nationwide registries in Germany

Introduction Pregnancy is a known independent risk factor for a severe course of COVID-19. The relationship of SARS-CoV-2 infection and gestational diabetes mellitus (GDM) on neonatal outcomes is unclear. Our aim was to determine if SARS-CoV-2 infection represents an independent risk factor for adverse perinatal outcomes in pregnancy with GDM.Research design and methods We compared data from two German registries including pregnant women with GDM, established during the SARS-CoV-2 pandemic (COVID-19-Related Obstetric and Neonatal Outcome Study (CRONOS), a multicenter prospective observational study) and already existing before the pandemic (German registry of pregnant women with GDM; GestDiab). In total, 409 participants with GDM and SARS-CoV-2 infection and 4598 participants with GDM, registered 2018–2019, were eligible for analyses. The primary fetal and neonatal outcomes were defined as: (1) combined: admission to neonatal intensive care unit, stillbirth, and/or neonatal death, and (2) preterm birth before 37+0 weeks of gestation. Large and small for gestational age, maternal insulin therapy, birth weight >4500 g and cesarean delivery were considered as secondary outcomes.Results Women with SARS-CoV-2 infection were younger (32 vs 33 years) and had a higher median body mass index (28 vs 27 kg/m²). In CRONOS, more neonates developed the primary outcome (adjusted OR (aOR) 1.48, 95% CI 1.11 to 1.97) and were born preterm (aOR 1.50, 95% CI 1.07 to 2.10). Fasting glucose was higher in women in CRONOS versus GestDiab (5.4 vs 5.3 mmol/L) considering each 0.1 mmol/L increase was independently associated with a 5% higher risk of preterm birth among women in CRONOS only (aOR 1.05, 95% CI 1.01 to 1.09).Conclusions GDM with SARS-CoV-2 infection in pregnancy is associated with an increased risk of adverse fetal and neonatal outcomes as compared with GDM without SARS-CoV-2 infection

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies

Spinal muscular atrophies (SMAs) are a heterogeneous group of disorders characterized by muscular atrophy, weakness, and hypotonia due to suspected lower motor neuron degeneration (LMND). In a large cohort of 3,465 individuals suspected with SMA submitted for SMN1 testing to our routine diagnostic laboratory, 48.8% carried a homozygous SMN1 deletion, 2.8% a subtle mutation, and an SMN1 deletion, whereas 48.4% remained undiagnosed. Recently, several other genes implicated in SMA/LMND have been reported. Despite several efforts to establish a diagnostic algorithm for non-5q-SMA (SMA without deletion or point mutations in SMN1 [5q13.2]), data from large-scale studies are not available. We tested the clinical utility of targeted sequencing in non-5q-SMA by developing two different gene panels. We first analyzed 30 individuals with a small panel including 62 genes associated with LMND using IonTorrent-AmpliSeq target enrichment. Then, additional 65 individuals were tested with a broader panel encompassing up to 479 genes implicated in neuromuscular diseases (NMDs) with Agilent-SureSelect target enrichment. The NMD panel provided a higher diagnostic yield (33%) than the restricted LMND panel (13%). Nondiagnosed cases were further subjected to exome or genome sequencing. Our experience supports the use of gene panels covering a broad disease spectrum for diseases that are highly heterogeneous and clinically difficult to differentiate