filamin A mutation

Zhenfeng Mao, Fumihiko Nakamura
Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding partners. FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2). The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit. FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres...
April 13, 2020: International Journal of Molecular Sciences
Arjan Sammani, Elham Kayvanpour, Laurens P Bosman, Farbod Sedaghat-Hamedani, Tanja Proctor, Weng-Tein Gi, Alicia Broezel, Katrin Jensen, Hugo A Katus, Anneline S J M Te Riele, Benjamin Meder, Folkert W Asselbergs
AIMS: Patients with non-ischaemic dilated cardiomyopathy (DCM) are at increased risk of sudden cardiac death. Identification of patients that may benefit from implantable cardioverter-defibrillator implantation remains challenging. In this study, we aimed to determine predictors of sustained ventricular arrhythmias in patients with DCM. METHODS AND RESULTS: We searched MEDLINE/Embase for studies describing predictors of sustained ventricular arrhythmias in patients with DCM...
April 14, 2020: ESC Heart Failure
Job A J Verdonschot, Els K Vanhoutte, Godelieve R F Claes, Apollonia T J M Helderman-van den Enden, Janneke G J Hoeijmakers, Debby M E I Hellebrekers, Amber de Haan, Imke Christiaans, Ronald H Lekanne Deprez, Hanne M Boen, Emeline M van Craenenbroeck, Bart L Loeys, Yvonne M Hoedemakers, Carlo Marcelis, Marlies Kempers, Esther Brusse, Jaap I van Waning, Annette F Baas, Dennis Dooijes, Folkert W Asselbergs, Daniela Q C M Barge-Schaapveld, Pieter Koopman, Arthur van den Wijngaard, Stephane R B Heymans, Ingrid P C Krapels, Han G Brunner
Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene...
February 29, 2020: Human Mutation
Emma M Wade, Benjamin J Halliday, Zandra A Jenkins, Adam C O'Neill, Stephen P Robertson
The X-linked filaminopathies represent a diverse group of clinical conditions, all caused by variants in the gene FLNA. FLNA encodes the widely expressed actin binding protein, filamin A that has multiple roles during embryonic development including cell migration, mechanical sensing, and cell signalling. In this review we discuss the ten distinct X-linked filaminopathy conditions that between them, affect almost all organ systems, including the brain, skeleton, heart, and skin, highlighting the critical role of this protein in human development...
February 27, 2020: Human Mutation
Nida S Iqbal, Thomas A Jascur, Steven M Harrison, Angelena B Edwards, Luke T Smith, Erin S Choi, Michelle K Arevalo, Catherine Chen, Shaohua Zhang, Adam J Kern, Angela E Scheuerle, Emma J Sanchez, Chao Xing, Linda A Baker
BACKGROUND: Prune belly syndrome (PBS) is a rare, multi-system congenital myopathy primarily affecting males that is poorly described genetically. Phenotypically, its morbidity spans from mild to lethal, however, all isolated PBS cases manifest three cardinal pathological features: 1) wrinkled flaccid ventral abdominal wall with skeletal muscle deficiency, 2) urinary tract dilation with poorly contractile smooth muscle, and 3) intra-abdominal undescended testes. Despite evidence for a genetic basis, previously reported PBS autosomal candidate genes only account for one consanguineous family and single cases...
February 21, 2020: BMC Medical Genetics
Longbo Zhang, Tianxiang Huang, Shannon Teaw, Lena H Nguyen, Lawrence S Hsieh, Xuan Gong, Lindsay H Burns, Angélique Bordey
Epilepsy treatments for patients with mechanistic target of rapamycin (mTOR) disorders, such as tuberous sclerosis complex (TSC) or focal cortical dysplasia type II (FCDII), are urgently needed. In these patients, the presence of focal cortical malformations is associated with the occurrence of lifelong epilepsy, leading to severe neurological comorbidities. Here, we show that the expression of the actin cross-linking protein filamin A (FLNA) is increased in resected cortical tissue that is responsible for seizures in patients with FCDII and in mice modeling TSC and FCDII with mutations in phosphoinositide 3-kinase (PI3K)-ras homolog enriched in brain (Rheb) pathway genes...
February 19, 2020: Science Translational Medicine
Yoon Jin Cha, Se Hoon Kim, Na Rae Kim
Background: The revised 4th 2016 World Health Organization (WHO) classification of tumors of the central nervous system (CNS) classification has adopted integrated diagnosis encompassing the histology and molecular features of CNS tumors. We aimed to investigate the immunohistochemistry, molecular testing, and testing methods for diagnosis of CNS tumors in pathological labs of tertiary centers in Korea, and evaluate the adequacy of tests for proper diagnosis in daily practice. Methods: A survey, composed of eight questions concerning molecular testing for diagnosis of CNS tumors, was sent to 10 neuropathologists working in tertiary centers in Korea...
February 20, 2020: Journal of Pathology and Translational Medicine
I Joksic, G Cuturilo, A Jurisic, S Djuricic, B Peterlin, M Mijovic, Orlic N Karadzov, A Egic, Z Milovanovic
Otopalatodigital spectrum disorder (OPDSD) is rare group of X-linked disorders caused by mutations in the filamin A ( FLNA ) gene. It is characterized by skeletal dysplasia of variable severity and different extra skeletal manifestations. Its presentation in the fetal period is quite unspecific, so diagnosis is usually made after birth. We present prenatal ultrasonography and postmortem findings that led us to a diagnosis of the mildest form of OPDSD (OPD type I) in two consecutive pregnancies. This is the first report on prenatal diagnosis (PND) of OPD type I...
December 2019: Balkan Journal of Medical Genetics: BJMG
Charlotte L Hall, Priyatansh Gurha, Maria Sabater-Molina, Angeliki Asimaki, Marta Futema, Ruth C Lovering, Mari Paz Suárez, Beatriz Aguilera, Pilar Molina, Esther Zorio, Cristian Coarfa, Matthew J Robertson, Sirisha M Cheedipudi, Keat-Eng Ng, Paul Delaney, Juan Pedro Hernández, Francisco Pastor, Juan R Gimeno, William J McKenna, Ali J Marian, Petros Syrris
Arrhythmogenic cardiomyopathy (ACM) encompasses a group of inherited cardiomyopathies including arrhythmogenic right ventricular cardiomyopathy (ARVC) whose molecular disease mechanism is associated with dysregulation of the canonical WNT signalling pathway. Recent evidence indicates that ARVC and ACM caused by pathogenic variants in the FLNC gene encoding filamin C, a major cardiac structural protein, may have different molecular mechanisms of pathogenesis. We sought to identify dysregulated biological pathways in FLNC-associated ACM...
December 6, 2019: International Journal of Cardiology
M Akhtar, P M Elliott
PURPOSE OF REVIEW: Non-ischaemic dilated cardiomyopathy (DCM) occurs in 1 in 2500 individuals in the general population and is associated with considerable morbidity and mortality. Studies involving large numbers of unselected DCM patients have led to consensus guidelines recommending implantable cardioverter-defibrillator (ICD) implantation for protection against sudden cardiac death (SCD) in those with LVEF ≤35%. The purpose of this article is to review the literature for other potential markers including serological, electrocardiographic, echocardiographic, cardiac magnetic resonance, ambulatory ECG and genetic data, to highlight other potential markers that may optimise risk stratification for SCD in this cohort and thereby allow a more personalized approach to ICD-implantation...
November 25, 2019: Current Cardiology Reports
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 that regulate 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. Thus, they connect adhesive receptors to signaling pathways and to cytoskeleton. There are 3 isoforms of FLN (filamin a [FLNa], FLNb, FLNc) that originate 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), heart (valve defect), skeleton, gastrointestinal tract, and, more recently, the megakaryocytic lineage...
October 17, 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 M 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...
March 1, 2020: 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
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