Min Liu, Zhangqi Xu, Cheng Zhang, Chunxia Yang, Jiaxing Feng, Yiqing Lu, Wen Zhang, Wenwen Chen, Xiaoyang Xu, Xiaoxia Sun, Mingyang Yang, Wei Liu, Tianhua Zhou, Yuehong Yang
Filamin A, the first discovered non-muscle actin filament cross-linking protein, plays a crucial role in regulating cell migration that participates in diverse cellular and developmental processes. However, the regulatory mechanism of filamin A stability remains unclear. Here, we find that nuclear distribution gene C (NudC), a cochaperone of heat shock protein 90 (Hsp90), is required to stabilize filamin A in mammalian cells. Immunoprecipitation-mass spectrometry and western blotting analyses reveal that NudC interacts with filamin A...
2021: Frontiers in Cell and Developmental Biology
Rudolf Andre Kley, Yvonne Leber, Bertold Schrank, Heidi Zhuge, Zacharias Orfanos, Julius Kostan, Adekunle Onipe, Dominik Sellung, Anne Katrin Güttsches, Britta Eggers, Frank Jacobsen, Wolfram Kress, Katrin Marcus, Kristina Djinovic-Carugo, Peter F M van der Ven, Dieter O Fürst, Matthias Vorgerd
Objective: To determine whether a new indel mutation in the dimerization domain of filamin C (FLNc) causes a hereditary myopathy with protein aggregation in muscle fibers, we clinically and molecularly studied a German family with autosomal dominant myofibrillar myopathy (MFM). Methods: We performed mutational analysis in 3 generations, muscle histopathology, and proteomic studies of IM protein aggregates. Functional consequences of the FLNC mutation were investigated with interaction and transfection studies and biophysics molecular analysis...
June 2021: Neurology. Genetics
Robert L Bowman, Rebecca C Hennessey, Tirzah J Weiss, David A Tallman, Emma R Crawford, Brandon M Murphy, Amy Webb, Souhui Zhang, Krista Md La Perle, Craig J Burd, Ross L Levine, A Hunter Shain, Christin E Burd
BRAF -mutant melanomas are more likely than NRAS -mutant melanomas to arise in anatomical locations protected from chronic sun damage. We hypothesized that this discrepancy in tumor location is a consequence of the differential sensitivity of BRAF and NRAS -mutant melanocytes to ultraviolet light (UV)-mediated carcinogenesis. We tested this hypothesis by comparing the mutagenic consequences of a single neonatal, ultraviolet-AI (UVA; 340-400 nm) or ultraviolet-B (UVB; 280-390 nm) exposure in mouse models heterozygous for mutant Braf or homozygous for mutant Nras Tumor onset was accelerated by UVB, but not UVA, and the resulting melanomas contained recurrent mutations affecting the RING domain of MAP3K1 and Actin-binding domain of Filamin A...
September 2021: Life Science Alliance
Sashidar Bandaru, Chandu Ala, Alex-Xianghua Zhou, Levent M Akyürek
Filamin A (FLNA) is a large actin-binding cytoskeletal protein that is important for cell motility by stabilizing actin networks and integrating them with cell membranes. Interestingly, a C -terminal fragment of FLNA can be cleaved off by calpain to stimulate adaptive angiogenesis by transporting multiple transcription factors into the nucleus. Recently, increasing evidence suggests that FLNA participates in the pathogenesis of cardiovascular and respiratory diseases, in which the interaction of FLNA with transcription factors and/or cell signaling molecules dictate the function of vascular cells...
June 18, 2021: International Journal of Molecular Sciences
Thomas Roland-Billecart, Matthias Schlund, Ludovic Lauwers, Romain Nicot, Joel Ferri
Otopalatodigital syndrome spectrum disorders are caused by Filamin A (FLNA) gene mutations. Otopalatodigital syndrome spectrum disorders are a group of rare congenital skeletal dysplasia, with specific craniomaxillofacial features including otopalatodigital syndrome type 1 and type 2, Melnick-Needles syndrome, frontometaphyseal dysplasia, terminal osseous dysplasia with pigmentary defects. The authors describe cases of a young girl with Melnick-Needles syndrome and a young boy with frontometaphyseal dysplasia treated in the Oral and Maxillofacial Surgery Department...
June 28, 2021: Journal of Craniofacial Surgery
Suniti Misra, Shibnath Ghatak, Ricardo A Moreno-Rodriguez, Russell A Norris, Vincent C Hascall, Roger R Markwald
Background: Discoveries in the identification of transcription factors, growth factors and extracellular signaling molecules have led to the detection of downstream targets that modulate valvular tissue organization that occurs during development, aging, or disease. Among these, matricellular protein, periostin, and cytoskeletal protein filamin A are highly expressed in developing heart valves. The phenotype of periostin null indicates that periostin promotes migration, survival, and differentiation of valve interstitial cushion cells into fibroblastic lineages necessary for postnatal valve remodeling/maturation...
2021: Frontiers in Cell and Developmental Biology
Mariana A Argenziano, Mariana Burgos Angulo, Maliheh Najari Beidokhti, Jiajia Yang, Alexander C Bertalovitz, Thomas V McDonald
Dilated Cardiomyopathy (DCM) is one of the main causes of sudden cardiac death and heart failure and is the leading indication for cardiac transplantation worldwide. Mutations in different genes including TTN, MYH7, and LMNA, have been linked to the development of DCM. Here, we generated a human induced pluripotent stem cell (IPSC) line from a DCM patient with a familial history that carries a frameshift mutation in Filamin C (FLNC). The IPSCs show typical morphology of pluripotent cells, expression of pluripotency markers, normal karyotype, and in vitro capacity to differentiate into all three germ layers...
May 2021: Stem Cell Research
Kewei Zhang, Xiaomei Yin, Kaituo Shi, Shihua Zhang, Juan Wang, Shasha Zhao, Huan Deng, Cheng Zhang, Zihui Wu, Yuan Li, Xiangyu Zhou, Wensheng Deng
Site-directed mutagenesis for large plasmids is a difficult task that cannot easily be solved by the conventional methods used in many laboratories. In this study, we developed an effective method for Site-directed Mutagenesis for Large Plasmids (SMLP) based on a PCR technique. The SMLP method combines several effective approaches, including a high-efficiency DNA polymerase for the large DNA amplification, two independent PCR reactions and a fast recombinational ligation. Using this method, we have achieved a variety of mutants for the filamin A gene (7...
May 17, 2021: Scientific Reports
Jinlong Wu, Chengfeng Xu, Xin Guan, Da Ni, Xuhui Yang, Zhiyin Yang, Mingsong Wang
Background: Tumor mutation burden (TMB) and immune microenvironment are important determinants of prognosis and immunotherapeutic efficacy for cancer patients. The aim of the present study was to develop an immune signature to effectively predict prognosis and immunotherapeutic response in patients with lung squamous cell carcinoma (LUSC). Methods: TMB and immune microenvironment characteristics were comprehensively analyzed by multi-omics data in LUSC. The immune signature was further constructed and validated in multiple independent datasets by LASSO Cox regression analysis...
April 2021: Annals of Translational Medicine
Kaya Fukushima, Padmini Parthasarathy, Emma M Wade, Tim Morgan, Kalpana Gowrishankar, David M Markie, Stephen P Robertson
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...
April 5, 2021: Genes
Giovanni Meliota, Ugo Vairo, Romina Ficarella, Leonardo Milella, Maria Felicia Faienza, Gabriele D'Amato
BACKGROUND: Filamin A (FLNA) is an intracellular actin-binding protein, encoded by the FLNA gene, with a wide tissue expression. It is involved in several cellular functions, and extracellular matrix structuring. FLNA gene alterations lead to diseases with a wide phenotypic spectrum, such as brain periventricular nodular heterotopia (PVNH), cardiovascular abnormalities, skeletal dysplasia, and lung involvement. CLINICAL FINDINGS: We present the case of a female infant who showed at birth aortic valve stenosis and PVNH, and subsequently developed interstitial lung disease with severe pulmonary hypertension...
April 12, 2021: Advances in Neonatal Care: Official Journal of the National Association of Neonatal Nurses
Robyn T Rebbeck, Anna K Andrick, Sarah A Denha, Bengt Svensson, Piyali Guhathakurta, David D Thomas, Thomas S Hays, Adam W Avery
Numerous diseases are linked to mutations in the actin-binding domains (ABDs) of conserved cytoskeletal proteins, including β-III-spectrin, α-actinin, filamin, and dystrophin. A β-III-spectrin ABD mutation (L253P) linked to spinocerebellar ataxia type 5 (SCA5) causes a dramatic increase in actin binding. Reducing actin binding of L253P is thus a potential therapeutic approach for SCA5 pathogenesis. Here, we validate a high-throughput screening (HTS) assay to discover potential disrupters of the interaction between the mutant β-III-spectrin ABD and actin in live cells...
December 24, 2020: Journal of Biological Chemistry
Jisup Kim, Jee-Young Park, Su-Jin Shin, Beom Jin Lim, Heounjeong Go
Background : Frameshift indels have emerged as a predictor of immunotherapy response but were not evaluated yet to predict anti-angiogenetic agent (AAA) response or prognosis in clear cell renal cell carcinoma (ccRCC). Methods : Here, to develop biomarkers that predict survival and response to AAA, we evaluated the immunohistochemical expression of proteins whose genes frequently harbor frameshift indels in 638 ccRCC patients and correlated the individual and integrated markers with prognosis and AAA response...
March 10, 2021: Cancers
Suet Nee Chen, Luisa Mestroni, Matthew R G Taylor
PURPOSE OF REVIEW: Dilated cardiomyopathy (DCM), which include genetic and nongenetic forms, is the most common form of cardiomyopathy. DCM is characterized by left ventricular or biventricular dilation with impaired contraction. In the United States, DCM is a burden to healthcare that accounts for approximately 10,000 deaths and 46,000 hospitalizations annually. In this review, we will focus on the genetic forms of DCM and on recent advances in the understanding of cytoskeletal, sarcomeric, desmosomal, nuclear membrane, and RNA binding genes that contribute to the complexity and genetic heterogeneity of DCM...
March 23, 2021: Current Opinion in Cardiology
Pankaj Pathak, Yotam Blech-Hermoni, Kalpana Subedi, Jessica Mpamugo, Charissa Obeng-Nyarko, Rachel Ohman, Ilda Molloy, Malcolm Kates, Jessica Hale, Stacey Stauffer, Shyam K Sharan, Ami Mankodi
Mechanical stress induced by contractions constantly threatens the integrity of muscle Z-disc, a crucial force-bearing structure in striated muscle. The PDZ-LIM proteins have been proposed to function as adaptors in transducing mechanical signals to preserve the Z-disc structure, however the underlying mechanisms remain poorly understood. Here, we show that LDB3, a well-characterized striated muscle PDZ-LIM protein, modulates mechanical stress signaling through interactions with the mechanosensing domain in filamin C, its chaperone HSPA8, and PKCα in the Z-disc of skeletal muscle...
March 19, 2021: Communications Biology
Amit S Shah, Emily D Black, Dawn M Simon, Michael J Gambello, Kathryn B Garber, Glen J Iannucci, Erica L Riedesel, Ajay S Kasi
Background: Interstitial lung disease (ILD) has been recently reported in a few patients with pathogenic variants in the Filamin A ( FLNA ) gene with variable presentation and prognosis. This study evaluated the respiratory manifestations and clinical features in children with FLNA disease. Methods: We conducted a retrospective review of pediatric patients with variants in FLNA in a tertiary children's hospital. The clinical features, genotype, management, and outcomes were analyzed. Results: We identified 9 patients with variants in FLNA aged 15 months to 24 years, 4 females and 5 males...
March 2021: Pediatric Allergy, Immunology, and Pulmonology
Anne Schänzer, Elisabeth Schumann, Diana Zengeler, Lisann Gulatz, Giovanni Maroli, Uwe Ahting, Anke Sprengel, Sabine Gräf, Andreas Hahn, Christian Jux, Till Acker, Dieter O Fürst, Stefan Rupp, Julia Schuld, Peter F M van der Ven
Hypertrophic cardiomyopathy (HCM) often leads to heart failure. Mutations in sarcomeric proteins are most frequently the cause of HCM but in many patients the gene defect is not known. Here we report on a young man who was diagnosed with HCM shortly after birth. Whole exome sequencing revealed a mutation in the FLNC gene (c.7289C > T; p.Ala2430Val) that was previously shown to cause aggregation of the mutant protein in transfected cells. Myocardial tissue from patients with this mutation has not been analyzed before and thus, the underlying etiology is not well understood...
March 12, 2021: Journal of Muscle Research and Cell Motility
Victor Valentin, Jean-François Bervar, Catherine Vincent-Delorme, Thomas Smol, Lidwine Wemeau, Martine Remy, Olivier Le Rouzic, Cécile Chenivesse
Emphysema is a chronic respiratory disorder characterized by destruction of alveoli, usually due to cigarette smoking or exposure to noxious particles or gases. Dysfunction of proteins that are involved in lung development and maintenance, such as alpha-1 antitrypsin, also contributes to emphysema. Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton reorganization. Mutations in the FLNA gene classically lead to abnormal neuronal migration and connective and vascular tissue anomalies. Pulmonary manifestations consist of a wide range of pulmonary disorders that occur during infancy...
March 2021: Chest
Youying Mao, Ronen Schneider, Peter F M van der Ven, Marvin Assent, Keerthika Lohanadan, Verena Klämbt, Florian Buerger, Thomas M Kitzler, Konstantin Deutsch, Makiko Nakayama, Amar J Majmundar, Nina Mann, Tobias Hermle, Ana C Onuchic-Whitford, Wei Zhou, Nandini Nagarajan Margam, Roy Duncan, Jonathan Marquez, Mustafa Khokha, Hanan M Fathy, Jameela A Kari, Sherif El Desoky, Loai A Eid, Hazem Subhi Awad, Muna Al-Saffar, Shrikant Mane, Richard P Lifton, Dieter O Fürst, Shirlee Shril, Friedhelm Hildebrandt
Introduction: Most of the approximately 60 genes that if mutated cause steroid-resistant nephrotic syndrome (SRNS) are highly expressed in the glomerular podocyte, rendering SRNS a "podocytopathy." Methods: We performed whole-exome sequencing (WES) in 1200 nephrotic syndrome (NS) patients. Results: We discovered homozygous truncating and homozygous missense mutation in SYNPO2 (synaptopodin-2) (p.Lys1124∗ and p.Ala1134Thr) in 2 patients with childhood-onset NS...
February 2021: KI Reports
Matthias Eden, Norbert Frey
Over the past decades, there has been tremendous progress in understanding genetic alterations that can result in different phenotypes of human cardiomyopathies. More than a thousand mutations in various genes have been identified, indicating that distinct genetic alterations, or combinations of genetic alterations, can cause either hypertrophic (HCM), dilated (DCM), restrictive (RCM), or arrhythmogenic cardiomyopathies (ARVC). Translation of these results from "bench to bedside" can potentially group affected patients according to their molecular etiology and identify subclinical individuals at high risk for developing cardiomyopathy or patients with overt phenotypes at high risk for cardiac deterioration or sudden cardiac death...
February 4, 2021: Journal of Clinical Medicine
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