Nara S Higano, Robert P Thomen, James D Quirk, Heidie L Huyck, Andrew D Hahn, Sean B Fain, Gloria S Pryhuber, Jason C Woods
BACKGROUND: Alveolar development and lung parenchymal simplification are not well characterized in vivo in neonatal patients with respiratory morbidities, such as bronchopulmonary dysplasia (BPD). Hyperpolarized (HP) gas diffusion magnetic resonance imaging (MRI) is a sensitive, safe, nonionizing, and noninvasive biomarker for measuring airspace size in vivo but has not yet been implemented in young infants. OBJECTIVE: This work quantified alveolar airspace size via HP gas diffusion MRI in healthy and diseased explanted infant lung specimens, with comparison to histological morphometry...
November 11, 2020: Neonatology
Xiaoxian Deng, Shanshan Li, Qiu Qiu, Bowen Jin, Menghuan Yan, Yuanpin Hu, Yang Wu, Hongmei Zhou, Gangcheng Zhang, Xuan Zheng
BACKGROUND: Pediatric patients with genetic disorders have a higher incidence of pulmonary arterial hypertension (PAH) regardless of their heart defects. Filamin A (FLNA) mutation is recently recognized to be associated with pediatric pulmonary disorders, however, the clinical courses of PAH related to the mutation were reported in limited cases. Here, we presented a case and pooled data for better understanding of the correlation between FLNA mutation and pediatric PAH. CASE PRESENTATION: The patient was a 8-month-old female with repeated episodes of pneumonia...
November 3, 2020: BMC Pediatrics
Lida Wu, Quanyi Wang, Junzhong Gu, Huiyuan Zhang, Yuchun Gu
Apart from its ion channel properties, the Kir2.1 channel has been found in tumors and cancer cells to facilitate cancer cell motility. It is assumed that Kir2.1 might be associated with cell actin filament dynamics. With the help of structured illumination microscopy (SIM), we show that Kir2.1 overexpression promotes actin filament dynamics, cell invasion, and adhesion. Mutated Kir2.1 channels, with impaired membrane expression, present much weaker actin regulatory effects, which indicates that precise Kir2...
October 10, 2020: International Journal of Molecular Sciences
Julia Schuld, Zacharias Orfanos, Frédéric Chevessier, Britta Eggers, Lorena Heil, Julian Uszkoreit, Andreas Unger, Gregor Kirfel, Peter F M van der Ven, Katrin Marcus, Wolfgang A Linke, Christoph S Clemen, Rolf Schröder, Dieter O Fürst
Filamin C (FLNc) is mainly expressed in striated muscle cells where it localizes to Z-discs, myotendinous junctions and intercalated discs. Recent studies have revealed numerous mutations in the FLNC gene causing familial and sporadic myopathies and cardiomyopathies with marked clinical variability. The most frequent myopathic mutation, p.W2710X, which is associated with myofibrillar myopathy, deletes the carboxy-terminal 16 amino acids from FLNc and abolishes the dimerization property of Ig-like domain 24...
September 4, 2020: Acta Neuropathologica Communications
Chi Hoon Oh, Chang Ho Lee, So Young Kim, So-Young Lee, Hak Hoon Jun, Soonchul Lee
BACKGROUND: Melnick-Needles syndrome (MNS) is an extremely rare osteochondrodysplasia caused by a mutation of FLNA, the gene encoding filamin A. MNS is inherited in an X-linked dominant manner. In this study, we describe three members of the same family with MNS, who exhibited different phenotypic severity despite having an identical FLNA gene mutation. CASE PRESENTATION: The patient was 16 months old, with a history of delayed physical development, multiple upper respiratory infections and otitis media episodes...
August 19, 2020: BMC Pediatrics
Teresinha Evangelista, Xavière Lornage, Pierre G Carlier, Guillaume Bassez, Guy Brochier, Anais Chanut, Emmanuelle Lacène, Mai-Thao Bui, Corinne Metay, Ursula Oppermann, Johann Böhm, Jocelyn Laporte, Norma B Romero
Autosomal dominant pathogenic variants in the filamin C gene (FLNC) have been associated with myofibrillar myopathies, distal myopathies, and isolated cardiomyopathies. Mutations in different functional domains of FLNC can cause various clinical phenotypes. A novel heterozygous missense variant c.608G>A, p.(Cys203Tyr) in the actin binding domain of FLCN was found to cause an upper limb distal myopathy (MIM #614065). The muscle MRI findings are similar to those observed in FLNC-myofibrillar myopathy (MIM #609524)...
June 30, 2020: Journal of Neuropathology and Experimental Neurology
Xiaowei Li, Yanyu Lu, Jiaxiang Wang, Mengduan Liu, Mengyu Wang, Liang Hu, Wenting Du, Lu Wang, Zhengming Jiang, Xiangmei Gu, Zhongren Ding, Deguang Feng, Ling Li, Jianzeng Dong, Xiaoyan Zhao
FLNA gene encodes an actin-binding protein filamin A and mutations in FLNA can causes X-Linked cardiac valvular dysplasia. In this study, we report the generation of ZZUNEUi008-A, a human induced pluripotent stem cell line from a 10-year-old male patient with c. 84G → A in FLNA gene using non-integrative Sendai viral reprogramming technology. The ZZUNEUi008-A iPSC line expresses pluripotency markers, exhibits a normal male karyotype (46, XY) and can differentiate into three germ layers in vivo.
June 22, 2020: Stem Cell Research
Shimrit Oz, Hagith Yonath, Leonid Visochyk, Efrat Ofek, Natalie Landa, Haike Reznik-Wolf, Martin Ortiz-Genga, Lorenzo Monserrat, Tuvia Ben-Gal, Orly Goitein, Roy Beinart, Michael Glikson, Dov Freimark, Elon Pras, Michael Arad, Eyal Nof
BACKGROUND: Filamin C is a cytoskeletal protein expressed in cardiac cells. Nonsense variations in the filamin C gene (FLNC) were associated with dilated and arrhythmogenic cardiomyopathies. METHODS AND RESULTS: We identified an intronic variation in FLNC gene (c.3791-1G > C) in three unrelated Ashkenazi Jewish families with variable expression of arrhythmia and cardiomyopathy. cDNA was prepared from a mutation carrier's cultured skin fibroblasts. Quantitative PCR demonstrated a reduction in total FLNC transcript, and no other FLNC splice variants were found...
April 5, 2020: International Journal of Cardiology
Heike Kölbel, Andreas Roos, Peter F M van der Ven, Teresinha Evangelista, Kay Nolte, Katherine Johnson, Ana Töpf, Michael Wilson, Wolfram Kress, Albert Sickmann, Volker Straub, Laxmikanth Kollipara, Joachim Weis, Dieter O Fürst, Ulrike Schara
Filamin C (encoded by the FLNC gene) is a large actin-cross-linking protein involved in shaping the actin cytoskeleton in response to signaling events both at the sarcolemma and at myofibrillar Z-discs of cross-striated muscle cells. Multiple mutations in FLNC are associated with myofibrillar myopathies of autosomal dominant inheritance. Here, we describe for the first time a boy with congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development but no cardiac involvement associated with a homozygous FLNC mutation c...
June 9, 2020: Human 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 signaling. In this review, we discuss the 10 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...
May 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
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