title: Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.
abstract: Phosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement. In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K. Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K. Downregulation of INPP5K orthologs in zebrafish embryos disrupted muscle fiber morphology and resulted in abnormal eye development. These data link congenital muscular dystrophies to defective phosphoinositide 5-phosphatase activity that is becoming increasingly recognized for its role in mediating pivotal cellular mechanisms contributing to disease.
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Wiessner
authors.affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; Leibniz-Institut für Analytische Wissenschaften (ISAS), 44227 Dortmund, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Roos
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Munn
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Ranjith
authors.initials: R
authors.lastname: Viswanathan
authors.affiliation: UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital for Children, London WC1N 1EH, UK; MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Tamieka
authors.initials: T
authors.lastname: Whyte
authors.affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Dan
authors.initials: D
authors.lastname: Cox
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
authors.affiliation: UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital for Children, London WC1N 1EH, UK; Wolfson Centre for Inherited Neuromuscular Disorders, RJAH Orthopaedic Hospital, Oswestry SY10 7AG, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.affiliation: Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham B9 5SS, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Roper
authors.affiliation: UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital for Children, London WC1N 1EH, UK.
authors.forename: Rahul
authors.initials: R
authors.lastname: Phadke
authors.affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Marini Bettolo
authors.affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; Rare Diseases Advisory Group Service for Neuromuscular Diseases, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Barresi
authors.affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; Rare Diseases Advisory Group Service for Neuromuscular Diseases, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Charlton
authors.affiliation: Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20814, USA.
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
authors.affiliation: Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20814, USA.
authors.forename: Osório
authors.initials: O
authors.lastname: Abath Neto
authors.affiliation: Departamento de Neurologia, Faculdade de Medicina da Universidade de São Paulo, 01246-903 São Paulo, Brazil.
authors.forename: Umbertina C
authors.initials: UC
authors.lastname: Reed
authors.affiliation: Departamento de Neurologia, Faculdade de Medicina da Universidade de São Paulo, 01246-903 São Paulo, Brazil.
authors.forename: Edmar
authors.initials: E
authors.lastname: Zanoteli
authors.affiliation: Departamento de Neurologia, Faculdade de Medicina da Universidade de São Paulo, 01246-903 São Paulo, Brazil.
authors.forename: Cristiane
authors.initials: C
authors.lastname: Araújo Martins Moreno
authors.affiliation: Institute for Clinical Radiology, Ludwig Maximilians University Munich, 81377 Munich, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Ertl-Wagner
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Stucka
authors.affiliation: Department of Paediatric Neurology, Royal Preston Hospital, Lancashire Teaching Hospitals NHS Foundation Trust, Preston PR2 9HT, UK; Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YG, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: De Goede
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
authors.forename: Tamiris
authors.initials: T
authors.lastname: Borges da Silva
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften (ISAS), 44227 Dortmund, Germany.
authors.forename: Denisa
authors.initials: D
authors.lastname: Hathazi
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften (ISAS), 44227 Dortmund, Germany.
authors.forename: Margherita
authors.initials: M
authors.lastname: Dell'Aica
authors.affiliation: Leibniz-Institut für Analytische Wissenschaften (ISAS), 44227 Dortmund, Germany.
authors.forename: René P
authors.initials: RP
authors.lastname: Zahedi
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Thiele
authors.affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Juliane
authors.initials: J
authors.lastname: Müller
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Kingston
authors.affiliation: Institute of Pathology, Ludwig-Maximilians University Munich, 80337 Munich, Germany.
authors.forename: Susanna
authors.initials: S
authors.lastname: Müller
authors.affiliation: Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Curtis
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilians University Munich, 80336 Munich, Germany.
authors.forename: Maggie C
authors.initials: MC
authors.lastname: Walter
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Kate
authors.initials: K
authors.lastname: Bushby
authors.affiliation: UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital for Children, London WC1N 1EH, UK; MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Swan
authors.affiliation: John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilians University Munich, 80336 Munich, Germany. Electronic address: jan.senderek@med.uni-muenchen.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D001921:Brain / Q000473:pathology; D002386:Cataract / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D060825:Cognitive Dysfunction / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics*; D009139:Musculoskeletal Abnormalities / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D055815:Young Adult; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: C471548:SKIP enzyme, human; D010744:Phosphoric Monoester Hydrolases
keywords: INPP5K; cognitive impairment; congenital muscular dystrophy; early cataracts; phosphoinositide phosphatase