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BACKGROUND: Filamin B (FLNB) can crosslink the actin cytoskeleton into a dynamic structure that is essential for the directional movement of cells. It can regulate the proliferation, differentiation and apoptosis of chondrocytes. However, the effect of FLNB on osteoblast proliferation, migration and apoptosis has not been reported. OBJECTIVE: To investigate the effect of FLNB on the proliferation, migration and apoptosis of MC3T3-E1 cells. METHODS: The adenoviral vectors for knockdown of FLNB expression (sh-FLNB1, sh-FLNB2, sh-FLNB3) were constructed and infected with MC3T3-E1 cells. After screened by puromycin drug, the efficiency of FLNB knockdown was detected by western blot and RT-PCR. The MC3T3-E1 cell line with the best efficiency of FLNB knockdown was selected as the stable transient cell line of MC3T3-E1 for subsequent experiments. The cells were divided into blank group, mc3t3 group, sh-NC group (empty vector), and sh-FLNB group (sh-FLNB lentivirus). The blank group was cultured in cell-free α-MEM complete medium; the mc3t3 group was cultured in α-MEM complete medium alone; and the sh-NC and sh-FLNB groups were cultured with α-MEM medium containing 2.5 μg/mL puromycin. After 3 days of culture, cell counting kit-8 assay and cell scratch assay were used to detect the proliferation and migration ability of MC3T3-E1; flow cytometry was used to detect cell apoptosis; and RT-PCR was used to detect the expression of apoptosis-related genes. RESULTS AND CONCLUSION: Western blot and RT-PCR results showed that the efficiency of FLNB knockdown was the best in the sh-FLNB3 (P < 0.000 1), which was used as a stable cell line for subsequent experiments. Cell counting kit-8 data showed that the proliferative ability of MC3T3 cells was significantly weakened after knockdown of FLNB (P < 0.05). Cell scratch assay results showed that the migration ability of MC3T3 cells was significantly decreased after knockdown of FLNB. Flow cytometry and RT-PCR results showed that the apoptotic rate of MC3T3-E1 cells increased after knockdown of FLNB, the expression of pro-apoptotic factor Bax increased significantly, and the expression of anti-apoptotic factor Bcl-2 decreased significantly (P < 0.05). To conclude, knockdown of FLNB can reduce the proliferation ability of MC3T3-E1 cells, decrease the migration ability of the cells, and increase cell apoptosis. [ABSTRACT FROM AUTHOR]

Objective: Filamin B (FLNB) encodes an actin-binding protein that is known to function as a novel RNA-binding protein involved in cell movement and signal transduction and plays a pivotal role in bone growth. This study aimed to investigate possible FLNB function in the skeletal system by characterizing the effecs of FLNB knockdown in mouse preosteoblast cells. Methods: Stable FLNB MC3T3-E1 knockdown cells were constructed for RNA-seq and alternative splicing event (ASE) analysis of genes involved in osteoblast differentiation and function that may be regulated by FLNB. Standard transwell, MTT, ALP, qPCR, Western blot, and alizarin red staining assays were used to assess functional changes of FLNB-knockdown MC3T3-E1 cells. Results: Analysis of differentially expressed genes (DEGs) in FLNB knockdown cells revealed enrichment for genes related to osteoblast proliferation, differentiation and migration, such as ITGA10, Cebpβ, Grem1, etc. Alternative splicing (AS) analysis showed changes in the predominant mRNA isoforms of skeletal development-related genes, especially Tpx2 and Evc. Functional asslysis indicated that proliferation, migration, and differentiation were all inhibited upon FLNB knockdown in MC3T3-E1 cells compared to that in vector control cells. Conclusions: FLNB participates in regulating the transcription and AS of genes required for osteoblast development and function, consequently affecting growth and development in MC3T3-E1 cells.

Vaccinia virus (VACV) is a large DNA virus that encodes scores of proteins that modulate the host immune response. VACV protein C4 is one such immunomodulator known to inhibit the activation of both the NF-κB signaling cascade and the DNA-PK-mediated DNA sensing pathway. Here, we show that the N-terminal region of C4, which neither inhibits NF-κB nor mediates interaction with DNA-PK, still contributes to virus virulence. Furthermore, this domain interacts directly and with high affinity to the C-terminal domain of filamin B (FLNB). FLNB is a large actin-binding protein that stabilizes the F-actin network and is implicated in other cellular processes. Deletion of FLNB from cells results in larger VACV plaques and increased infectious viral yield, indicating that FLNB restricts VACV spread. These data demonstrate that C4 has a new function that contributes to virulence and engages the cytoskeleton. Furthermore, we show that the cytoskeleton performs further previously uncharacterized functions during VACV infection. [ABSTRACT FROM AUTHOR]

Filamin B (FLNB) plays an important role in skeletal development. Mutations in FLNB can lead to skeletal malformation such as an abnormal number of ossification centers, indicating that the skeletal segmentation in the embryonic period may be interfered with. We established a mouse model with the pathogenic point mutation FLNB NM_001081427.1: c.4756G > A (p.Gly1586Arg) using CRISPR-Cas9 technology. Micro-CT, HE staining and whole skeletal preparation were performed to examine the skeletal malformation. In situ hybridization of embryos was performed to examine the transcription of HOX genes during embryonic development. The expression of FLNB was downregulated in FLNBG1586R/G1586R and FLNBWT/G1586R mice, compared to FLNBWT/WT mice. Fusions in tarsal bones were found in FLNBG1586R/G1586R and FLNBWT/G1586R mice, indicating that the skeletal segmentation was interfered with. In the embryo of FLNBG1586R/G1586R mice (E12.5), the transcription levels of HOXD10 and HOXB2 were downregulated in the carpal region and cervical spine region, respectively. This study indicated that the loss-of-function mutation G1586R in FLNB may lead to abnormal skeletal segmentation, and the mechanism was possibly associated with the downregulation of HOX gene transcription during the embryonic period.

Objective: Filamin B (FLNB) encodes an actin-binding protein that is known to function as a novel RNA-binding protein involved in cell movement and signal transduction and plays a pivotal role in bone growth. This study aimed to investigate possible FLNB function in the skeletal system by characterizing the effecs of FLNB knockdown in mouse preosteoblast cells., Methods: Stable FLNB MC3T3-E1 knockdown cells were constructed for RNA-seq and alternative splicing event (ASE) analysis of genes involved in osteoblast differentiation and function that may be regulated by FLNB. Standard transwell, MTT, ALP, qPCR, Western blot, and alizarin red staining assays were used to assess functional changes of FLNB-knockdown MC3T3-E1 cells., Results: Analysis of differentially expressed genes (DEGs) in FLNB knockdown cells revealed enrichment for genes related to osteoblast proliferation, differentiation and migration, such as ITGA10, Cebpβ, Grem1, etc. Alternative splicing (AS) analysis showed changes in the predominant mRNA isoforms of skeletal development-related genes, especially Tpx2 and Evc. Functional asslysis indicated that proliferation, migration, and differentiation were all inhibited upon FLNB knockdown in MC3T3-E1 cells compared to that in vector control cells., Conclusions: FLNB participates in regulating the transcription and AS of genes required for osteoblast development and function, consequently affecting growth and development in MC3T3-E1 cells., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Authors.)

Objective: In the present study we aim to evaluate whether some of the proteins previously identified in the secretome of senescent bone marrow (BM)- and adipose (A)-mesenchymal stromal cells (MSCs) could be involved in regulation of senescence phenomena. Materials and Methods: Among the identified proteins, we selected Filamin B (FLNB) and Aminopeptidase N (CD13) that were exclusively found in the secretome of senescent cells. We silenced their mRNA expression in BM-MSCs by means of RNA interference technology and induced acute senescence by hydrogen peroxide treatment. Our goal was to evaluate if FLNB or CD13 silencing may affect onset of senescence. Results: Our preliminary data showed that CD13 protein could be a key factor involved in the regulation and determination of both primary and paracrine induced senescence in human BM-MSCs. On the other hand, Filamin B seems not to be involved in the determination of primary senescence whereas its presence could be part of the mechanism that regulates the senescence induction in human BM-MSCs by paracrine signaling. Conclusion: Our study provides a useful base for identifying the complex extracellular protein networks involved in the regulation of MSC cellular senescence.

Filamin B (FLNB) plays an important role in skeletal development. Mutations in FLNB can lead to skeletal malformation such as an abnormal number of ossification centers, indicating that the skeletal segmentation in the embryonic period may be interfered with. We established a mouse model with the pathogenic point mutation FLNB NM&#95;001081427.1: c.4756G > A (p.Gly1586Arg) using CRISPR-Cas9 technology. Micro-CT, HE staining and whole skeletal preparation were performed to examine the skeletal malformation. In situ hybridization of embryos was performed to examine the transcription of HOX genes during embryonic development. The expression of FLNB was downregulated in FLNB G1586R/G1586R and FLNB WT/G1586R mice, compared to FLNB WT/WT mice. Fusions in tarsal bones were found in FLNB G1586R/G1586R and FLNB WT/G1586R mice, indicating that the skeletal segmentation was interfered with. In the embryo of FLNB G1586R / G1586R mice (E12.5), the transcription levels of HOXD10 and HOXB2 were downregulated in the carpal region and cervical spine region, respectively. This study indicated that the loss-of-function mutation G1586R in FLNB may lead to abnormal skeletal segmentation, and the mechanism was possibly associated with the downregulation of HOX gene transcription during the embryonic period., Competing Interests: Lijia Cui, Yude Lin, Leigh-Anne Cui, Weibo Xia, Qiming Xu declare no conflict of interest., (© 2024 Published by Elsevier Inc.)

Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formation. FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs (NSOFCs). Here, we report two rare heterozygous variants (p.P441T and p.G565R) in FLNB in two unrelated hereditary families with NSOFCs. Bioinformatics analysis suggests that both variants may disrupt the function of FLNB. In mammalian cells, p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB, suggesting that they are loss-of-function mutations. Immunohistochemistry analysis demonstrates that FLNB is abundantly expressed during palatal development. Importantly, Flnb -/- embryos display cleft palates and previously defined skeletal defects. Taken together, our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans., Competing Interests: Conflict of interest The authors declare that they have no conflict of interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: In the present study we aim to evaluate whether some of the proteins previously identified in the secretome of senescent bone marrow (BM)- and adipose (A)-mesenchymal stromal cells (MSCs) could be involved in regulation of senescence phenomena. Materials and Methods: Among the identified proteins, we selected Filamin B (FLNB) and Aminopeptidase N (CD13) that were exclusively found in the secretome of senescent cells. We silenced their mRNA expression in BM-MSCs by means of RNA interference technology and induced acute senescence by hydrogen peroxide treatment. Our goal was to evaluate if FLNB or CD13 silencing may affect onset of senescence. Results: Our preliminary data showed that CD13 protein could be a key factor involved in the regulation and determination of both primary and paracrine induced senescence in human BM-MSCs. On the other hand, Filamin B seems not to be involved in the determination of primary senescence whereas its presence could be part of the mechanism that regulates the senescence induction in human BM-MSCs by paracrine signaling. Conclusion: Our study provides a useful base for identifying the complex extracellular protein networks involved in the regulation of MSC cellular senescence. [ABSTRACT FROM AUTHOR]

Adenosine to inosine RNA editing in protein-coding messenger RNAs (mRNAs) potentially leads to changes in the amino acid composition of the encoded proteins. The mRNAs encoding the ubiquitously expressed actin-crosslinking proteins Filamin A and Filamin B undergo RNA editing leading to a highly conserved glutamine to arginine exchange at the identical position in either protein. Here, by targeted amplicon sequencing we analysed the RNA editing of Filamin B across several mouse tissues during post-natal development. We find highest filamin B editing levels in skeletal muscles, cartilage and bones, tissues where Filamin B function seems most important. Through the analysis of Filamin B editing in mice deficient in either ADAR1 or 2, we identified ADAR2 as the enzyme responsible for Filamin B RNA editing. We show that in neuronal tissues Filamin B editing drops in spliced transcripts indicating regulated maturation of edited transcripts. We show further that the variability of Filamin B editing across several organs correlates with its mRNA expression. [ABSTRACT FROM AUTHOR]

Spondylocarpotarsal synostosis syndrome (SCTS) is characterized by intervertebral fusions and fusion of the carpal and tarsal bones. Biallelic mutations in FLNB cause this condition in some families, whereas monoallelic variants in MYH3 , encoding embryonic heavy chain myosin 3, have been implicated in dominantly inherited forms of the disorder. Here, five individuals without FLNB mutations from three families were hypothesized to be affected by recessive SCTS on account of sibling recurrence of the phenotype. Initial whole-exome sequencing (WES) showed that all five were heterozygous for one of two independent splice-site variants in MYH3 . Despite evidence indicating that three of the five individuals shared two allelic haplotypes encompassing MYH3 , no second variant could be located in the WES datasets. Subsequent genome sequencing of these three individuals demonstrated a variant altering a 5′ UTR splice donor site (rs557849165 in MYH3 ) not represented by exome-capture platforms. When the cohort was expanded to 16 SCTS-affected individuals without FLNB mutations, nine had truncating mutations transmitted by unaffected parents, and six inherited the rs557849165 variant in trans, an observation at odds with the population allele frequency for this variant. The rs557849165 variant disrupts splicing in the 5′ UTR but is still permissive of MYH3 translational initiation, albeit with reduced efficiency. Although some MYH3 variants cause dominant SCTS, these data indicate that others (notably truncating variants) do not, except in the context of compound heterozygosity for a second hypomorphic allele. These observations make genetic diagnosis challenging in the context of simplex presentations of the disorder. [ABSTRACT FROM AUTHOR]

Filamin B (FLNB) functions as a switch that can affect chrondrocyte development and endochondral bone formation through a series of signaling molecules and transcription factors that also affect Sertoli cell development. Here, we report a subject with a novel skeletal dysplasia and co‐existing 46,XY gonadal dysgenesis and biallelic mutations in FLNB. Whole exome sequencing was performed to identify mutations. Quantitative polymerase chain reaction (qPCR) and flow variant assays were performed to quantify RNA, proteins and phosphorylated proteins. The TOPFLASH reporter was performed to quantify β‐catenin activity. Mutations were identified in the FLNB gene (FLNB:p.F964L, FLNB:p.A1577V). These mutations increased binding of FLNB protein to the MAP3K1 and RAC1 signal transduction complex and activated β‐catenin and had different effects on phosphorylation of MAP kinase pathway intermediates and SOX9 expression. Direct activation of β‐catenin through the FLNB‐MAP3K1‐RAC1 complex by FLNB mutations is a novel mechanism for causing 46,XY gonadal dysgenesis. The mechanism of action varies from those reported previously for loss of function mutations in SOX9 and gain‐of‐function mutations in MAP3K1. [ABSTRACT FROM AUTHOR]

ABSTRACT Spondylocarpotarsal synostosis syndrome (SCT) is a distinct group of disorders characterized by short stature, disrupted vertebral segmentation with vertebral fusion, scoliosis, lordosis, carpal/tarsal synostosis, and lack of rib anomalies. Mutations in filamin B ( FLNB) and MYH3 have been reported for autosomal-recessive and autosomal-dominant SCT, respectively. We present a family with two patients suffering from autosomal-recessive SCT with rib anomalies, including malalignment, crowding, and uneven size and shape of ribs. Whole-exome sequencing revealed a novel p.S2542Lfs*82 (c.7621dup) frameshift mutation in FLNB. This frameshift mutation lies in the C-terminal-most domain involved in FLNB dimerization and resulted in a 20-residue elongation, with complete familial segregation and absence in 376 normal controls. The mutant p.S2542Lfs*82 FLNB demonstrated a complete loss of ability to form a functional dimer in transiently transfected HEK293T cells. The p.S2542Lfs*82 mutation also led to significantly reduced protein levels and accumulation of the mutant protein in the Golgi apparatus. This is the first identified mutation in the dimerization domain of FLNB. This loss-of-function frameshift mutation in FLNB causes autosomal-recessive SCT with rarely reported rib anomalies. This report demonstrates the involvement of rib anomaly in SCT and its causative mutation in the dimerization domain of FLNB. [ABSTRACT FROM AUTHOR]

Background Hypertrophic cardiomyopathy (HCM) is an autosomal-dominant disease with mutations in genes encoding sarcomeric proteins. Previous findings suggest deregulation of the ubiquitin proteasome system (UPS) in HCM in humans and in a mouse model of HCM ( Mybpc3 -targeted knock-in (KI) mice). In this study we investigated transcript levels of several muscle-specific E3 ubiquitin ligases in KI mice and aimed at identifying novel protein targets. Methods and Results Out of 9 muscle-specific E3 ligases, Asb2β was found with the lowest mRNA level in KI compared to wild-type (WT) mice. After adenoviral-mediated Asb2β transduction of WT neonatal mouse cardiomyocytes with either a WT or inactive Asb2β mutant, desmin was identified as a new target of Asb2β by mass spectrometry, co-immunoprecipitation and immunoblotting. Immunofluorescence analysis revealed a co-localization of desmin with Asb2β at the Z-disk of the sarcomere. Knock-down of Asb2β in cardiomyocytes resulted in higher desmin protein levels. Furthermore, desmin levels were higher in ventricular samples of HCM mice and patients than controls. Conclusions This study identifies desmin as a new Asb2β target for proteasomal degradation in cardiomyocytes and suggests that accumulation of desmin could contribute to UPS impairment in HCM mice and patients. [ABSTRACT FROM AUTHOR]

Spondylocarpotarsal synostosis syndrome (SCT) is a very rare skeletal dysplasia characterized by vertebral, carpal, and tarsal fusion; growth retardation; and mild dysmorphic facial features. Variants in FLNB, MYH3, and RFLNA have been implicated in this dysplasia. We report the clinical and radiological follow-up of seven SCT pediatric cases associated with biallelic FLNB variants, from four Argentinian families. The seven cases share previously described facial characteristics: round facies, large eyes, and wide based nose; all of them had variable height deficit, in one case noted early in life. Other findings included clinodactyly, joint limitation without bone fusion, neurosensorial hearing loss, and ophthalmological compromise. All cases presented with spinal fusion with variable severity and location, carpal bones coalition, and also delay in carpal ossification. The heterozygous carrier parents had normal height values to -2.5 score standard deviation, without skeletal defects detected. Three different FLNB variants, one nonsense and two frameshift, were detected, all of which were predicted to result in a truncated protein or are degraded by nonsense mediated decay. All cases had at least one copy of the nonsense variant, c.1128C> G; p. (Tyr376*), suggesting the presence of a common ancestor., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Background Low bone mineral density (BMD) is a primary risk factor for osteoporosis and is a highly heritable trait, but appears to be influenced by many genes. Genome-wide linkage studies have highlighted the chromosomal region 3p14-p22 as a quantitative trait locus for BMD (LOD 1.1 - 3.5). The FLNB gene, which is thought to have a role in cytoskeletal actin dynamics, is located within this chromosomal region and presents as a strong candidate for BMD regulation. We have previously identified significant associations between four SNPs in the FLNB gene and BMD in women. We have also previously identified associations between five SNPs located 5' of the transcription start site (TSS) and in intron 1 of the FLNB gene and expression of FLNB mRNA in osteoblasts in vitro. The latter five SNPs were genotyped in this study to test for association with BMD parameters in a family-based population of 769 Caucasian women. Results Using FBAT, significant associations were seen for femoral neck BMD Z-score with the SNPs rs11720285, rs11130605 and rs9809315 (P = 0.004 - 0.043). These three SNPs were also found to be significantly associated with total hip BMD Z-score (P = 0.014 - 0.026). We then combined the genotype data for these three SNPs with the four SNPs we previously identified as associated with BMD and performed a conditional analysis to determine whether they represent multiple independent associations with BMD. The results from this analysis suggested that these variants represent a single association signal. Conclusions The SNPs identified in our studies as associated with BMD appear to be part of a single association signal between the FLNB gene and BMD in our data. FLNB is one of several genes located in 3p14-p22 that has been identified as significantly associated with BMD in Caucasian women. [ABSTRACT FROM AUTHOR]

We report a case of an infant with unique and unreported combinations of brain anomalies. The patient showed distinctive facial findings, severe delay in psychomotor development, cranial nerve palsy and seizures. Brain magnetic resonance imaging performed at 5 days of age revealed complex brain malformations, including heterotopia around the mesial wall of lateral ventricles, dysmorphic cingulate gyrus, and enlarged midbrain tectum. The patient unexpectedly died at 13 months of age. Postmortem pathological findings included a polymicrogyric cingulate cortex, periventricular nodular heterotopia, basal ganglia and thalamic anomalies, and dysmorphic midbrain tectum. Potential candidate genes showed no abnormalities by traditional PCR-based sequencing. Whole-exome sequencing confirmed the presence of novel gene variants for filamin B ( FLNB), guanylate binding protein family member 6, and chromosome X open reading frame 59, which adapt to the autosomal recessive mode or X-linked recessive mode. Although immunohistochemical analysis confirmed the expression of FLNB protein in the vessel walls and white matter in autopsied specimens, there may be functional relevance of the compound heterozygous FLNB variants during brain development. [ABSTRACT FROM AUTHOR]

Most of our knowledge regarding glioma cell biology comes from cell culture experiments. For many years the standards for glioma cell culture were the use of cell lines cultured in the presence of serum and 20 % O2. However, in vivo, normoxia in many brain areas is in close to 3 % O2. Hence, in cell culture, the experimental value referred as the norm is hyperoxic compared to any brain physiological value. Likewise, cells in vivo are not usually exposed to serum, and low-passaged glioma neurosphere cultures maintained in serum-free medium is emerging as a new standard. A consequence of changing the experimental normoxic standard from 20 % O2 to the more brain physiological value of 3 % O2, is that a 3 % O2 normoxic reference point enabled a more rigorous characterization of the level of regulation of genes by hypoxia. Among the glioma hypoxia-regulated genes characterized using this approach we found VE- cadherin that is required for blood vessel formation, and filamin B a gene involved in endothelial cell motility. Both VE-cadherin and filamin B were found expressed in pseudopalisades, a glioblastoma pathognomonic structure made of hypoxic migrating cancer cells. These results provide additional clues on the role played by hypoxia in the acquisition of endothelial traits by glioma cells and on the functional links existing between pseudopalisades, hypoxia, and tumor progression. [ABSTRACT FROM AUTHOR]

Boomerang dysplasia is a rare lethal osteochondrodysplasia characterized by disorganized mineralization of the skeleton, leading to complete nonossification of some limb bones and vertebral elements, and a boomerang-like aspect to some of the long tubular bones. Like many short-limbed skeletal dysplasias with accompanying thoracic hypoplasia, the potential lethality of the phenotype can be difficult to ascertain prenatally. We report a case of boomerang dysplasia prenatally diagnosed by use of ultrasonography and 3D-CT imaging, and identified a novel mutation in the gene encoding the cytoskeletal protein filamin B (FLNB) postmortem. Findings that aided the radiological diagnosis of this condition in utero included absent ossification of two out of three long bones in each limb and elements of the vertebrae and a boomerang-like shape to the ulnae. The identified mutation is the third described for this disorder and is predicted to lead to amino acid substitution in the actin-binding domain of the filamin B molecule. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the effects of polymorphisms within the filamin B (FLNB) gene on bone mineral density (BMD) in women and on gene expression in osteoblasts from in vitro studies. The study enrolled 767 female sibs in which the chromosome 3p14-p21 linkage with BMD was previously shown. It found that prevalent fractures were increased in carriers of the A allele of rs7637505. Findings of the study also suggest common variants in FLNB effects on bone structure in women.

Larsen syndrome is an autosomal-dominant disorder characterized by multiple joint dislocations, vertebral anomalies and dysmorphic facies. Both autosomal-dominant and autosomal-recessive forms of the disorder have been proposed. Individuals with autosomal-dominant Larsen syndrome have characteristic "cylindrical-shape" thumbs caused by broad, shortened phalanges. Autosomal-dominant Larsen syndrome results from heterozygosity for mutations in filamin B, a cytoskeletal protein involved in multicellular processes. We report here a patient with a duplicated or accessory distal thumb phalanx and multiple large joint dislocations who was shown to be heterozygous for a filamin B mutation predicting the amino acid substitution G1691S. This adds a new radiographic finding, duplicated or accessory distal phalanx, to the radiographic abnormalities seen in this rare dominant disorder. [ABSTRACT FROM AUTHOR]

Spondylocarpotarsal synostosis syndrome (SCT) is characterized by vertebral fusions, a disproportionately short stature, and synostosis of carpal and tarsal bones. Pathogenic variants in FLNB, MYH3, and possibly in RFLNA, have been reported to be responsible for this condition. Here, we present two unrelated individuals presenting with features typical of SCT in which Sanger sequencing combined with whole genome sequencing identified novel, homozygous intragenic deletions in FLNB (c.1346-1372_1941+389del and c.3127-353_4223-1836del). Both deletions remove several consecutive exons and are predicted to result in a frameshift. To our knowledge, this is the first time that large structural variants in FLNB have been reported in SCT, and thus our findings add to the classes of variation that can lead to this disorder. These cases highlight the need for copy number sensitive methods to be utilized in order to be comprehensive in the search for a molecular diagnosis in individuals with a clinical diagnosis of SCT. [ABSTRACT FROM AUTHOR]

Spondylocarpotarsal synostosis (SS) is a disorder of abnormal vertebral segmentation. Clinically manifest as kyphoscoliosis/scoliosis with characteristic radiographic findings vertebral, carpal and tarsal bone fusion. It is inherited as an autosomal recessive disorder. The present study report a case of SS and describe the clinical and radiological manifestations. In addition to classical signs, neuroimaging revealed cervical spine abnormalities, further supporting the importance of spine imaging in such cases [ABSTRACT FROM AUTHOR]

Post‑transcriptional mechanisms are an important approach in the treatment of cancer, and may also be hijacked by tumor cells to help adapt to the local microenvironment. Filamin B (FLNB), an actin‑binding protein that provides crucial scaffolds for cell motility and signaling, has also been identified as an RNA‑binding protein. Recent studies demonstrated that FLNB might play an important role, not only in skeletal development, but also in regulating tumorigenesis; however, the effects of dysregulated expression of FLNB at the molecular level are not clear. In the present study, RNA‑sequencing was performed to analyze changes in overall transcriptional and alternative splicing between the knocked‑down FLNB and the control in HeLa cells. Decreased FLNB levels resulted in significantly lower apoptosis compared with control cells. FLNB knockdown extensively regulated the expression of genes in cell apoptosis, tumorigenesis, metastases, transmembrane transport and cartilage development. Moreover, FLNB regulated alternative splicing of a large number of genes involved in 'cell death' and the 'apoptotic process'. Some genes and alternative splicing related to skeletal development were enriched and regulated by FLNB. Reverse transcription‑quantitative‑PCR identified FLNB‑regulated transcription and alternative splicing of genes, such as NLR family apoptosis inhibitory protein, interleukin 23 subunit α, metastasis associated lung adenocarcinoma transcript 1, phosphofurin acidic cluster sorting protein 2, bone morphogenetic protein 7, matrix metallopeptidase 13, collagen type II α 1 chain, fibroblast growth factor receptor 2 and vitamin D receptor. The present study is the first study, to the best of the authors' knowledge, to provide transcriptome‑wide analysis of differential gene expression and alternative splicing upon FLNB silencing. The present results suggested that FLNB may play an important regulatory role in cervical cancer cell apoptosis via regulation of transcription and alternative splicing, which provide insight for the current understanding of the mechanisms of FLNB‑mediated gene regulation.

Objectives: The purpose of this study was to investigate the expression of Filamin b in the placental placenta of patients with early or late onset pre-eclampsia (PE) and its potential effects on the pathophysiology of the disease., Methods and Methods: Immunohistochemistry staining, western blot assays and real time PCR were used to detect the expression level of FLN-b. The expression levels of MMP-2, MMP-9 and ERK1/2 proteins from control and FLN-b-silenced JEG-3 cells were also detected by western blot and JEG-3 cell invasion., Results: Compared with normal term pregnancies placentas, the FLN-b expression was significantly lower than that of women with PE, its level in late-onset PE is lower than in early-onset PE. In FLN-b-silenced JEG-3 cells, the protein levels of MMP-2, MMP-9 and phosphorylated ERK1/2 decreased markedly and the number of cells penetrating through the transwell chamber membrane is also greatly reduced., Conclusions: Down-regulation of FLN-b inhibits the ERK/MMP-2 and MMP-9 pathways, leading to trophoblastic invasion disorders in the PE placenta.

Filamin B (FLNB) is a large dimeric actin-binding protein which crosslinks actin cytoskeleton filaments into a dynamic structure. Up to present, pathogenic mutations in FLNB are solely found to cause skeletal deformities, indicating the important role of FLNB in skeletal development. FLNB-related disorders are classified as spondylocarpotarsal synostosis (SCT), Larsen syndrome (LS), atelosteogenesis (AO), boomerang dysplasia (BD), and isolated congenital talipes equinovarus, presenting with scoliosis, short-limbed dwarfism, clubfoot, joint dislocation and other unique skeletal abnormalities. Several mechanisms of FLNB mutations causing skeletal malformations have been proposed, including delay of ossification in long bone growth plate, reduction of bone mineral density (BMD), dysregulation of muscle differentiation, ossification of intervertebral disc (IVD), disturbance of proliferation, differentiation and apoptosis in chondrocytes, impairment of angiogenesis, and hypomotility of osteoblast, chondrocyte and fibroblast. Interventions on FLNB-related diseases require prenatal surveillance by sonography, gene testing in high-risk carriers, and proper orthosis or orthopedic surgeries to correct malformations including scoliosis, cervical spine instability, large joint dislocation, and clubfoot. Gene and cell therapies for FLNB-related diseases are also promising but require further studies., (Copyright © 2017 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.)