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7 results on '"PSMD12"'

1. Thyroarytenoid muscle gene expression in a rat model of early-onset Parkinson’s disease

Author

Heidi Kletzien, Stephen C. Gammie, Cynthia A. Kelm-Nelson, and Sarah A. Lechner

Subjects
0301 basic medicine, Male, Parkinson's disease, PINK1, Vocal Cords, Bioinformatics, medicine.disease_cause, Article, PPM1B, 03 medical and health sciences, Gene Knockout Techniques, 0302 clinical medicine, Loss of Function Mutation, Gene expression, medicine, Animals, Humans, Thyroarytenoid muscle, Gene, Mutation, Voice Disorders, business.industry, Gene Expression Profiling, Parkinson Disease, medicine.disease, Rats, Disease Models, Animal, 030104 developmental biology, Otorhinolaryngology, Quality of Life, PSMD12, Laryngeal Muscles, Rats, Transgenic, Vocalization, Animal, business, Protein Kinases, 030217 neurology & neurosurgery
Abstract

OBJECTIVES/HYPOTHESIS Voice disorders in Parkinson's disease (PD) are early-onset, manifest in the preclinical stages of the disease, and negatively impact quality of life. The complete loss of function in the PTEN-induced kinase 1 gene (Pink1) causes a genetic form of early-onset, autosomal recessive PD. Modeled after the human inherited mutation, the Pink1-/- rat demonstrates significant cranial sensorimotor dysfunction including declines in ultrasonic vocalizations. However, the underlying genetics of the vocal fold thyroarytenoid (TA) muscle that may contribute to vocal deficits has not been studied. The aim of this study was to identify differentially expressed genes in the TA muscle of 8-month-old male Pink1-/- rats compared to wildtype controls. STUDY DESIGN Animal experiment with control. METHODS High throughput RNA sequencing was used to examine TA muscle gene expression in adult male Pink1-/- rats and wildtype controls. Weighted Gene Co-expression Network Analysis was used to construct co-expression modules to identify biological networks, including where Pink1 was a central node. The ENRICHR tool was used to compare this gene set to existing human gene databases. RESULTS We identified 134 annotated differentially expressed genes (P

Published
2021

2. PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features

Author

Stacey Gabriel, Ganeshwaran H. Mochida, Connor J. Kenny, Raida Khalil, Lihadh Al-Gazali, Christopher A. Walsh, Jennifer N. Partlow, R. Sean Hill, Ramzi Nasir, Brenda J. Barry, Christine Stevens, Maria H. Chahrour, Jay W. Ellison, A. James Barkovich, Muna Al-Saffar, and Chloe Egan

Subjects
Adult, Male, 0301 basic medicine, Proteasome Endopeptidase Complex, Adolescent, Autism Spectrum Disorder, Nonsense mutation, Neurogenetics, Haploinsufficiency, Biology, medicine.disease_cause, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Neurodevelopmental disorder, Intellectual Disability, Exome Sequencing, medicine, Humans, Family, Genetic Predisposition to Disease, Autistic Disorder, Child, Genetics (clinical), Exome sequencing, Genetics, Mutation, Siblings, medicine.disease, Pedigree, Psychiatry and Mental health, 030104 developmental biology, Neurodevelopmental Disorders, Autism spectrum disorder, Child, Preschool, Female, PSMD12
Abstract

Protein homeostasis is tightly regulated by the ubiquitin proteasome pathway. Disruption of this pathway gives rise to a host of neurological disorders. Through whole exome sequencing (WES) in families with neurodevelopmental disorders, we identified mutations in PSMD12, a core component of the proteasome, underlying a neurodevelopmental disorder with intellectual disability (ID) and features of autism spectrum disorder (ASD). We performed WES on six affected siblings from a multiplex family with ID and autistic features, the affected father, and two unaffected mothers, and a trio from a simplex family with one affected child with ID and periventricular nodular heterotopia. We identified an inherited heterozygous nonsense mutation in PSMD12 (NM_002816: c.367C>T: p.R123X) in the multiplex family and a de novo nonsense mutation in the same gene (NM_002816: c.601C>T: p.R201X) in the simplex family. PSMD12 encodes a non-ATPase regulatory subunit of the 26S proteasome. We confirm the association of PSMD12 with ID, present the first cases of inherited PSMD12 mutation, and demonstrate the heterogeneity of phenotypes associated with PSMD12 mutations.

Published
2018
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3. Expanding the clinical and molecular spectrum of psmd12-related neurodevelopmental syndrome: an additional patient and review

Author

Pietro Palumbo, Nenad Bukvic, Stefano Castellana, Tommaso Mazza, Orazio Palumbo, Valentina Leotta, Maria Pia Leone, Ester Di Muro, Tommaso Biagini, and Massimo Carella

Subjects
next generation sequencing, Genetic heterogeneity, Mechanism (biology), neurodevelopmental disorders, Neurogenesis, Regulator, General Medicine, Biology, medicine.disease, missense variant, ubiquitin-proteasome system, PSMD12, Speech delay, Intellectual disability, medicine, Missense mutation, medicine.symptom, Neuroscience
Abstract

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process that eukaryotic cells use to regulate their functions and coordinate their signaling networks. In particular, it plays a crucial role in neuronal development regulating very important functional and morphological interplays of neurons, such as synaptic plasticity, neurotransmitter release and morphogenesis of axons. Pathogenic alterations of genes involved in the proteolysis by UPS have been associated with several neurodevelopmental disorders (NDDs) and human diseases, highlighting the importance of this regulatory mechanism to developmental processes and neurogenesis. Here, we describe a 19 years old male patient showing a syndromic form of NDD. The main clinical features are intellectual disability/speech delay, congenital anomalies and facial dysmorphisms. Through a targeted resequencing approach (TRS), we identified a missense variant in PSMD12, a gene recently associated to an emerging syndromic form of NDD, which encodes for the non-ATPase subunit of the 19S regulator of 26S proteasome complex. The variant described herein, inherited from the father with apparently borderline cognitive ability, is useful to expand the molecular spectrum of heterozygous PSMD12 mutations and to provide insight into the molecular pathogenesis of this new condition since it is, to the best of our knowledge, the first missense substitution to date reported in medical literature. More importantly, our study highlight once again the utility of next generation sequencing in establishing an etiological basis in clinically and genetically heterogeneous conditions such as NDDs, thus allowing a better diagnosis, counseling and management of affected patients and their families.

Published
2019

4. Association of 17q24.2-q24.3 deletions with recognizable phenotype and short telomeres

Author

Michaela Kotrova, Miroslava Hancarova, Jana Drabova, Marcela Malíková, Zdenek Sedlacek, and Marie Trkova

Subjects
0301 basic medicine, Developmental Disabilities, Eczema, Hypertrichosis, 030105 genetics & heredity, Biology, 03 medical and health sciences, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Dubowitz syndrome, Child, Gene, Carney complex, Genetics (clinical), Growth Disorders, Fibromatosis, Gingival, Facies, Telomere, medicine.disease, Phenotype, 030104 developmental biology, Face, Speech delay, Microcephaly, Female, PSMD12, medicine.symptom, Chromosome Deletion, Chromosomes, Human, Pair 17
Abstract

Microdeletions of 17q24.2-q24.3 have been described in several patients with developmental and speech delay, growth retardation, and other features. The relatively large size and limited overlap of the deletions complicate the genotype-phenotype correlation. We identified a girl with intellectual disability, growth retardation, dysmorphic features, and a de novo 2.8 Mb long deletion of 17q24.2-q24.3. Her phenotype was strikingly similar to one previously described boy with Dubowitz syndrome (MIM 223370) and a de novo 3.9 Mb long deletion encompassing the deletion of our patient. In addition, both patients had the shortest telomeres among normal age-matched controls. Our review of all 17q24.2-q24.3 deletion patients revealed additional remarkable phenotypic features shared by the patients, some of which have consequences for their management. Proposed novel genotype-phenotype correlations based on new literature information on the region include the role of PSMD12 and BPTF, the genes recently associated with syndromic neurodevelopmental disorders, and a possible role of the complex topologically associated domain structure of the region, which may explain some of the phenotypic discrepancies observed between patients with similar but not identical deletions. Nevertheless, although different diagnoses including the Dubowitz, Nijmegen breakage (MIM 251260), Silver-Russell (MIM 180860), or Myhre (MIM 139210) syndromes were originally considered in the 17q24.2-q24.3 deletion patients, they clearly belong to one diagnostic entity defined by their deletions and characterized especially by developmental delay, specific facial dysmorphism, abnormalities of extremities and other phenotypes, and possibly also short telomere length.

Published
2017

5. Prenatal Diagnosis of a 2.5 Mb De Novo 17q24.1q24.2 Deletion Encompassing KPNA2 and PSMD12 Genes in a Fetus with Craniofacial Dysmorphism, Equinovarus Feet, and Syndactyly

Author

Sophie Brisset, Lucie Tosca, Gérard Tachdjian, Julien Saada, Virginie Benoit, Loïc Drévillon, Marie-Emmanuelle Naud, Jelena Martinovic, and Corinne Metay

Subjects
0301 basic medicine, Genetics, Fetus, Pathology, medicine.medical_specialty, lcsh:QH426-470, business.industry, Prenatal diagnosis, Case Report, General Medicine, 030105 genetics & heredity, medicine.disease, Phenotype, 03 medical and health sciences, lcsh:Genetics, 030104 developmental biology, Intellectual disability, medicine, Syndactyly, PSMD12, business, Gene, Craniofacial dysmorphism
Abstract

Interstitial 17q24.1 or 17q24.2 deletions were reported after conventional cytogenetic analysis or chromosomal microarray analysis in patients presenting intellectual disability, facial dysmorphism, and/or malformations. We report on a fetus with craniofacial dysmorphism, talipes equinovarus, and syndactyly associated with a de novo 2.5 Mb 17q24.1q24.2 deletion. Among the deleted genes, KPNA2 and PSMD12 are discussed for the correlation with the fetal phenotype. This is the first case of prenatal diagnosis of 17q24.1q24.2 deletion.

Published
2017

6. De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Author

Jill A. Rosenfeld, Dominique Bonneau, Deborah Barbouth, Stephen Sanders, Kimberly Nugent, Kimberly Glaser, Ignacio Briceño, Kyle Retterer, Sylvain Simon, Weimin Bi, Yaping Yang, Holly A.F. Stessman, Kristin G. Monaghan, Pawel Stankiewicz, Caroline Rooryck, Sébastien Küry, James R. Lupski, Xenia Latypova, Carlos A. Bacino, Stephanie Sacharow, Sandra Mercier, Evan E. Eichler, Marie Vincent, Elizabeth Roeder, Sébastien Schmitt, Thomas Besnard, Alberto Gómez, Ankita Patel, Brigitte Gilbert-Dussardier, Valérie Malan, Mathilde Nizon, Jessica Douglas, Annick Toutain, Peter-Michael Kloetzel, Anne-Sophie Denommé-Pichon, Frédéric Ebstein, Fan Xia, Laurent Pasquier, Megan T. Cho, Mathilde Pacault, Laurence Perrin-Sabourin, James B. Gibson, Bertrand Isidor, William J. Craigen, Bo Yuan, Stéphane Bézieau, Chad A. Shaw, Richard Redon, Janice L. Smith, Benjamin Cogné, Eric Bieth, Wallid Deb, Kamal Khan, Sylvie Odent, Andrea Lehmann, Tahir N. Khan, Philippe Parent, Christelle Golzio, Nicholas Katsanis, Marie-Line Jacquemont, Tomasz Gambin, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Boston Children's Hospital, Department of Medicine, Karolinska Institutet [Stockholm], Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Department of Pediatrics, The University of Texas at San Antonio (UTSA), LabEX IGO Immunothérapie Grand Ouest, Service de Cancéro-Dermatologie, Centre hospitalier universitaire de Nantes (CHU Nantes), Anti-tumor immunosurveillances and immunotherapy (CRCINA - Département INCIT - Equipe 3), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, CHU Pontchaillou [Rennes], Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Instituto de Genetica Humana, Pontificia Universidad Javeriana, Universitad de la Sabana, Baylor College of Medicine (BCM), Baylor University, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for Human Disease Modeling, Duke University [Durham], National Heart, Lung, and Blood Institute, Wellcome Trust, French Ministry of Health, HUGODIMS, 2013, RC14_0107, Health Regional Agency from Poitou-Charentes, U54HG006542, US National Human Genome Research Institute, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Duke University Medical Center, Warsaw University of Technology [Warsaw], University of California [San Francisco] (UC San Francisco), University of California (UC), University of Miami, Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Robert Debré, GeneDx [Gaithersburg, MD, USA], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Nantes Université (Nantes Univ), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Biologie Neurovasculaire Intégrée [Angers] (CNRS UMR6214 - INSERM U771), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pontificia Universidad Javeriana (PUJ), University of Washington [Seattle], Howard Hughes Medical Institute [Seattle], Howard Hughes Medical Institute (HHMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Jonchère, Laurent, Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), The University of Texas at San Antonio ( UTSA ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Anti-tumor immunosurveillances and immunotherapy ( CRCINA - Département INCIT - Equipe 3 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université d'Angers ( UA ) -CHU Angers, Centre hospitalier universitaire de Poitiers ( CHU Poitiers ) -Centre de Référence Anomalies du Développement Ouest, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Hôpital Bretonneau-CHRU Tours, Université de Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Universidad de la Sabana, Baylor College of Medicine ( BCM ), Baylor College of Medicine, unité de recherche de l'institut du thorax UMR1087 UMR6291 ( ITX ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Duke university [Durham]

Subjects
Male, 0301 basic medicine, Microcephaly, Intellectual disability, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, 0302 clinical medicine, Neurodevelopmental disorder, Ubiquitin, PSMD12, Syndromic neurodevelopmental disorder, Child, Zebrafish, Genetics (clinical), Genetics, Proteasome 26S, Phenotype, proteasome 26S, intellectual disability, Child, Preschool, Female, Proteasome Endopeptidase Complex, Adolescent, DNA Copy Number Variations, syndromic neurodevelopmental disorder, Protein subunit, Down-Regulation, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Report, RPN5, ubiquitin, medicine, Animals, Humans, [SDV.GEN]Life Sciences [q-bio]/Genetics, Point mutation, Infant, Correction, biology.organism_classification, medicine.disease, Human genetics, Disease Models, Animal, 030104 developmental biology, Proteasome, Neurodevelopmental Disorders, biology.protein, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Gene Deletion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

12 páginas Trichosporon asahii es un hongo patógeno emergente reportado en la literatura médica principalmente en pacientes inmunocomprometidos. No obstante, el presente caso es inusual debido a que se trata de un paciente adulto joven inmunocompetente que presentó fungemia por T. asahii y al mismo tiempo desarrolló insuficiencia respiratoria aguda por bronquiolitis respiratoria y neumonía descamativa, la cual resolvió posterior al tratamiento antimicótico instaurado, soporte ventilatorio y vigilancia en Unidad de Cuidado Intesivo (UCI). Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.

Published
2017
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7. Interaction of amyotrophic lateral sclerosis/frontotemporal lobar degeneration-associated fused-in-sarcoma with proteins involved in metabolic and protein degradation pathways

Author

Gang Chen, Jin Xu, Tao Wang, and Xin Jiang

Subjects
Aging, Juvenile amyotrophic lateral sclerosis, Cell Cycle Proteins, Protein degradation, Biology, Interactome, Adenosine Triphosphate, Valosin Containing Protein, medicine, Humans, Protein Interaction Maps, RNA, Messenger, Nuclear protein, Amyotrophic lateral sclerosis, Genetics, Adenosine Triphosphatases, General Neuroscience, Amyotrophic Lateral Sclerosis, Frontotemporal lobar degeneration, medicine.disease, Cell biology, HEK293 Cells, Proteasome, Proteolysis, RNA-Binding Protein FUS, Mutant Proteins, Neurology (clinical), Geriatrics and Gerontology, PSMD12, Frontotemporal Lobar Degeneration, Energy Metabolism, Developmental Biology, Protein Binding
Abstract

Fused-in-sarcoma (FUS) is a nuclear protein linked to amyotrophic lateral sclerosis and frontotemporal dementia. Under pathologic conditions, FUS frequently is accumulated in cytosoplasm, but how this altered distribution affects the protein interaction pattern of FUS is unclear. Using dual-tag affinity purification and mass spectrometry, we compared the interactome of the wild-type FUS and the P525 L mutant, which causes juvenile amyotrophic lateral sclerosis with the most severe phenotypes. The mutant FUS retained the ability to bind proteins involved in RNA metabolism. We found significant increased binding of P525 L to many metabolic enzymes. Furthermore, we identified and confirmed some novel interactions between FUS and proteins involved in neurodegenerative diseases and/or ubiquitin proteasome pathway, such as VCP/p97, PSF, UBA 1, and 26S proteosome non-ATPase regulatory subunit 12 (PSMD12/Rpn5). Accordingly, we have observed significantly reduced ATP levels and increased accumulation of poly-ubiquitinated proteins in cells with FUS accumulation. Therefore, our study suggested new mechanisms whereby FUS accumulation leads to defective energy metabolism and protein degradation by directly interacting with key regulators in these pathways. (C) 2015 Elsevier Inc. All rights reserved.

Published
2014

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