filamin A mutation

Yuan Zhao, Hongyuan Wang, Richard J Poole, David Gems
Differences in genetic background in model organisms can have complex effects on phenotypes of interest. We previously reported a difference in hermaphrodite lifespan between two wild-type lines widely used by C. elegans researchers (N2 hermaphrodite and male stocks). Here, using pathology-based approaches and genome sequencing, we identify the cause of this difference as a nonsense mutation in the filamin gene fln-2 in the male stock, which reduces early mortality caused by pharyngeal infection. We show how fln-2 variation explains previous discrepancies involving effects of sir-2...
November 8, 2019: Nature Communications
Charlotte L Hall, Mohammed M Akhtar, Maria Sabater-Molina, Marta Futema, Angeliki Asimaki, Alexandros Protonotarios, Chrysoula Dalageorgou, Alan M Pittman, Mari Paz Suarez, Beatriz Aguilera, Pilar Molina, Esther Zorio, Juan Pedro Hernández, Francisco Pastor, Juan R Gimeno, Petros Syrris, William J McKenna
BACKGROUND: Pathogenic variants in the filamin C (FLNC) gene are associated with inherited cardiomyopathies including dilated cardiomyopathy with an arrhythmogenic phenotype. We evaluated FLNC variants in arrhythmogenic cardiomyopathy (ACM) and investigated the disease mechanism at a molecular level. METHODS: 120 gene-elusive ACM patients who fulfilled diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC) were screened by whole exome sequencing...
October 8, 2019: International Journal of Cardiology
Babken Asatryan, Helge Servatius
The Expanding Phenotype Spectrum of ARVC: First described by the Italian physician and anatomist Giovanni Maria Lancisi in 1728, Arrhythmogenic right ventricular cardiomyopathy (ARVC) is recognized as a genetic heart disease with a progressive course and a high risk of sudden cardiac death (SCD). In the advanced stages, this disease is characterized pathologically by fibrofatty replacement of the right ventricular myocardium. However, ARVC commonly manifests with life-threatening ventricular arrhythmias in early stages prior to development of the robust structural heart disease...
September 22, 2019: Circulation. Genomic and precision medicine
Tatu J K Haataja, Romain Capoulade, Simon Lecointe, Maarit Hellman, Jean Merot, Perttu Permi, Ulla Pentikäinen
Mitral valve diseases affect ∼3% of the population and are the most common reasons for valvular surgery because no drug-based treatments exist. Inheritable genetic mutations have now been established as the cause of mitral valve insufficiency, and four different missense mutations in the filamin A gene (FLNA) have been found in patients suffering from nonsyndromic mitral valve dysplasia (MVD). The filamin A (FLNA) protein is expressed, in particular, in endocardial endothelia during fetal valve morphogenesis and is key in cardiac development...
August 31, 2019: Biophysical Journal
Laura Montier, Zulfi Haneef, Jay Gavvala, Daniel Yoshor, Robert North, Terence Verla, Paul C Van Ness, Janice Drabek, Alica M Goldman
Periventricular nodular heterotopia (PNH) is a common structural malformation of cortical development. Mutations in the filamin A gene are frequent in familial cases with X-linked PNH. However, many cases with sporadic PNH remain genetically unexplained. Although medically refractory epilepsy often brings attention to the underlying PNH, patients are often not candidates for surgical resection. This limits access to neuronal tissue harboring causal mutations. We evaluated a patient with PNH and medically refractory focal epilepsy who underwent a presurgical evaluation with stereotactically placed electroencephalographic (SEEG) depth electrodes...
October 2019: Epilepsia
Jean-Philippe Rosa, Hana Raslova, Marijke Bryckaert
Filamins (FLNs) are large dimeric actin binding proteins regulating actin cytoskeleton remodeling. In addition FLNs serve as scaffolds for signaling proteins such as tyrosine kinases, GTPases or phosphatases, as well as for adhesive receptors such as integrins. They thus connect adhesive receptors to signaling pathways and to cytoskeleton. There are 3 isoforms of FLNs (FLNa, FLNb, FLNc) originating from 3 homologous genes. FLNa has been the recent focus of attention because its mutations are responsible for a wide spectrum of defects, called filaminopathies A, affecting brain (peri-ventricular nodular heterotopia or PVNH), heart (valve defect), skeleton, gastro-intestinal tract or more recently, the megakaryocytic lineage...
August 30, 2019: Blood
Gloria Pelizzo, Maria A Avanzini, Elisa Lenta, Melissa Mantelli, Stefania Croce, Laura Catenacci, Gloria Acquafredda, Aurelio L Ferraro, Caterina Giambanco, Lucia D'Amelio, Salvatore Giordano, Giuseppe Re, Floriana Zennaro, Valeria Calcaterra
BACKGROUND: Mesenchymal stromal cell (MSC)-mediated therapeutic effects have been observed in the treatment of lung diseases. For the first time, this treatment was used as rescue therapy in a pediatric patient with a life-threatening respiratory syndrome associated with the filamin A (FLNA) gene mutation. METHODS: A child with a new pathogenic variant of the FLNA gene c.7391_7403del (p.Val2464AlafsTer5), at the age of 18 months, due to serious and irreversible chronic respiratory failure, was treated with repeated intravenous infusions of allogeneic bone marrow (BM)-MSCs...
August 29, 2019: Pediatric Pulmonology
Juanjuan Chen, Jun Wu, Chunxi Han, Yao Li, Yuzu Guo, Xiaoxin Tong
BACKGROUND: Myofibrillar myopathies (MFMs) are a genetically heterogeneous group of muscle disorders. Mutations in the filamin C gene (FLNC) have previously been identified in patients with MFM. The phenotypes of FLNC-related MFM are heterogeneous. CASE PRESENTATION: The patient was a 37-year-old male who first experienced weakness in the distal muscles of his hand, which eventually spread to the lower limbs and proximal muscles. Serum creatine kinase levels were moderately elevated...
August 17, 2019: BMC Neurology
João B Augusto, Rocio Eiros, Eleni Nakou, Sara Moura-Ferreira, Thomas A Treibel, Gabriella Captur, Mohammed A Akhtar, Alexandros Protonotarios, Thomas D Gossios, Konstantinos Savvatis, Petros Syrris, Saidi Mohiddin, James C Moon, Perry M Elliott, Luis R Lopes
AIMS : Myocardial scar detected by cardiovascular magnetic resonance has been associated with sudden cardiac death in dilated cardiomyopathy (DCM). Certain genetic causes of DCM may cause a malignant arrhythmogenic phenotype. The concepts of arrhythmogenic left ventricular (LV) cardiomyopathy (ALVC) and arrhythmogenic DCM are currently ill-defined. We hypothesized that a distinctive imaging phenotype defines ALVC. METHODS AND RESULTS : Eighty-nine patients with DCM-associated mutations [desmoplakin (DSP) n = 25, filamin C (FLNC) n = 7, titin n = 30, lamin A/C n = 12, bcl2-associated athanogene 3 n = 3, RNA binding motif protein 20 n = 3, cardiac sodium channel NAv1...
July 16, 2019: European Heart Journal Cardiovascular Imaging
Yan Liu, Li Wang, Yi-Ke Yang, Ying Liang, Tie-Juan Zhang, Na Liang, Li-Man Yang, Si-Jing Li, Dan Shan, Qing-Qing Wu
BACKGROUND: This study aims to provide genetic diagnoses for 30 cases of fetal skeletal dysplasia, and a molecular basis for the future prenatal diagnosis of fetal skeletal dysplasia. METHODS: A total of 30 cases of fetal skeletal dysplasia detected with ultrasound between January 2014 and June 2017 were analyzed. Among these fetuses, 15 fetuses had local skeletal malformations, while 15 fetuses had short limb malformations. Samples of fetal umbilical cord blood, amniotic fluid, and/or aborted tissue were collected from all cases...
July 13, 2019: Diagnostic Pathology
Miranda P Collier, T Reid Alderson, Carin P de Villiers, Daisy Nicholls, Heidi Y Gastall, Timothy M Allison, Matteo T Degiacomi, He Jiang, Georg Mlynek, Dieter O Fürst, Peter F M van der Ven, Kristina Djinovic-Carugo, Andrew J Baldwin, Hugh Watkins, Katja Gehmlich, Justin L P Benesch
Mechanical force-induced conformational changes in proteins underpin a variety of physiological functions, typified in muscle contractile machinery. Mutations in the actin-binding protein filamin C (FLNC) are linked to musculoskeletal pathologies characterized by altered biomechanical properties and sometimes aggregates. HspB1, an abundant molecular chaperone, is prevalent in striated muscle where it is phosphorylated in response to cues including mechanical stress. We report the interaction and up-regulation of both proteins in three mouse models of biomechanical stress, with HspB1 being phosphorylated and FLNC being localized to load-bearing sites...
May 2019: Science Advances
Jalal Gharesouran, Behnaz Salek Esfahani, Saeed Farajzadeh Valilou, Mohsen Moradi, Mir Hadi Mousavi, Maryam Rezazadeh
Congenital short bowel syndrome (CSBS) is a rare congenital neonatal disorder. CSBS results from intestinal impairment during embryogenesis. Mutated CXADR-like membrane protein ( CLMP ) and Filamin A genes are involved in the cause of CSBS. In this study, due to our misdiagnosis, we had to perform whole exome sequencing on the patient, and also we implemented cosegregation analysis on his parents with consanguineous marriage and also parents' mothers. We identified a homozygous loss of function mutation in the CLMP gene in exon 5 (c...
June 2019: Journal of Pediatric Genetics
Fumihiko Nakamura, Lina Wang
Filamin A (FLNA) is a ubiquitously expressed actin across-linking protein and a scaffold of numer-ous binding partners to regulate cell proliferation, migration, and survival. FLNA is a homodimer, and each subunit has a N-terminal actin-binding domain followed by 24 immunoglobulin-like re-peats (R). FLNA mediates mechanotransduction by force-induced conformational changes of its cryptic integrin-binding site on R21. Here, we identified two novel FLNA-binding partners, smoothelins (SMTN A and B) and leucine zipper protein 1 (LUZP1), using stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics followed by in silico screening for proteins having consensus FLNA-binding domain...
April 16, 2019: Biochemistry
Keisuke Yoshii, Hideki Matsumoto, Kyoko Hirasawa, Masako Sakauchi, Hiroko Hara, Susumu Ito, Makiko Osawa, Maki Fukami, Reiko Horikawa, Satoru Nagata
Lung phenotype was reported as a novel phenotype in patients with mutations in the filamin A gene (FLNA) in 2011. FLNA mutations can result in pulmonary hyperinflation during the neonatal period or early infancy with progressive respiratory failure, culminating in a diagnosis of FLNA-associated progressive lung disease, particularly if the patient has periventricular nodular heterotopia and cardiac complications, such as patent ductus arteriosus, atrial septal defect, and pulmonary hypertension. We report the first Japanese case of FLNA-associated progressive lung disease caused by a microdeletion in Xq28 encompassing the FLNA gene with a polymorphic inversion...
April 12, 2019: Respiratory Investigation
Gloria Pelizzo, Mirella Collura, Aurora Puglisi, Maria Pia Pappalardo, Emanuele Agolini, Antonio Novelli, Maria Piccione, Caterina Cacace, Rossana Bussani, Giovanni Corsello, Valeria Calcaterra
BACKGROUND: Progressive lung involvement in Filamin A (FLNA)-related cerebral periventricular nodular heterotopia (PVNH) has been reported in a limited number of cases. CASE PRESENTATION: We report a new pathogenic FLNA gene variant (c.7391_7403del; p.Val2464Alafs*5) in a male infant who developed progressive lung disease with emphysematous lesions and interstitial involvement. Following lobar resection, chronic respiratory failure ensued necessitating continuous mechanical ventilation and tracheostomy...
March 29, 2019: BMC Pediatrics
Hitomi Shimizu, Satoshi Watanabe, Akira Kinoshita, Hiroyuki Mishima, Gen Nishimura, Hiroyuki Moriuchi, Koh-Ichiro Yoshiura, Sumito Dateki
Spondylocarpotarsal synostosis syndrome, a rare syndromic skeletal disorder characterized by disrupted vertebral segmentation with vertebral fusion, scoliosis, short stature, and carpal/tarsal synostosis, has been associated with biallelic truncating mutations in the filamin B gene or monoallelic mutations in the myosin heavy chain 3 gene. We herein report the case of a patient with a typical phenotype of spondylocarpotarsal synostosis syndrome who had a homozygous frameshift mutation in the refilin A gene (RFLNA) [c...
February 22, 2019: Journal of Human Genetics
Haitham Amal, Guanyu Gong, Elizabeta Gjoneska, Sarah M Lewis, John S Wishnok, Li-Huei Tsai, Steven R Tannenbaum
Mutations in the MAPT gene, which encodes the tau protein, are associated with several neurodegenerative diseases, including frontotemporal dementia (FTD), dementia with epilepsy, and other types of dementia. The missense mutation in the Mapt gene in the P301S mouse model of FTD results in impaired synaptic function and microgliosis at three months of age, which are the earliest manifestations of disease. Here, we examined changes in the S-nitrosoproteome in 2-month-old transgenic P301S mice in order to detect molecular events corresponding to early stages of disease progression...
January 29, 2019: Translational Psychiatry
Alessandro Donada, Nathalie Balayn, Dominika Sliwa, Larissa Lordier, Valentina Ceglia, Francesco Baschieri, Cyril Goizet, Rémi Favier, Lucie Tosca, Gérard Tachdjian, Cecile V Denis, Isabelle Plo, William Vainchenker, Najet Debili, Jean-Philippe Rosa, Marijke Bryckaert, Hana Raslova
Filamin A (FLNa) links the cell membrane with the cytoskeleton and is central in several cellular processes. Heterozygous mutations in the X-linked FLNA gene are associated with a large spectrum of conditions called filaminopathies that include macrothrombocytopenia. Here we show, using an isogenic pluripotent stem cell model derived from patients, that the absence of the FLNa protein in megakaryocytes (MKs) leads to their incomplete maturation, and particularly the inability to produce proplatelets. The reduction in the proplatelet formation potential is associated with a defect in the acto-myosin contractility, due to inappropriate RhoA activation...
January 2, 2019: Blood
Valeria Calcaterra, Maria Antonietta Avanzini, Melissa Mantelli, Emanuele Agolini, Stefania Croce, Annalisa De Silvestri, Giuseppe Re, Mirella Collura, Alice Maltese, Antonio Novelli, Gloria Pelizzo
RATIONALE: Mesenchymal stem cells (MSC) play a crucial role in both the maintenance of pulmonary integrity and the pathogenesis of lung disease. Lung involvement has been reported in patients with the filamin A (FLNA) gene mutation. Considering FLNA's role in the intrinsic mechanical properties of MSC, we characterized MSCs isolated from FLNA-defective lung tissue, in order to define their pathogenetic role in pulmonary damage. PATIENT CONCERNS: A male infant developed significant lung disease resulting in emphysematous lesions and perivascular and interstitial fibrosis...
December 2018: Medicine (Baltimore)
Erina Sasaki, Angela T Byrne, Ethna Phelan, Desmond W Cox, William Reardon
The filamin A gene (FLNA) on Xq28 encodes the filamin A protein. Mutation in FLNA causes a wide spectrum of disease including skeletal dysplasia, neuronal migration abnormality, cardiovascular malformation, intellectual disability and intestinal obstruction. Recently, childhood-onset interstitial lung disease associated with a range of FLNA mutations has been recognised and reported. We document our personal experience of this emerging disorder and compile a comprehensive overview of clinical features and molecular changes in all identifiable published cases...
December 13, 2018: European Journal of Pediatrics
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