Format

Send to

Choose Destination
Am J Hum Genet. 2017 Mar 2;100(3):523-536. doi: 10.1016/j.ajhg.2017.01.024. Epub 2017 Feb 9.

Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.

Author information

1
Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilians University Munich, 80336 Munich, Germany.
2
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.
3
Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.
4
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.
5
John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
6
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.
7
Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham B9 5SS, UK.
8
UCL Great Ormond Street Institute of Child Health & Great Ormond Street Hospital for Children, London WC1N 1EH, UK.
9
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.
10
Neuromuscular and Neurogenetic Disorders of Childhood Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20814, USA.
11
Departamento de Neurologia, Faculdade de Medicina da Universidade de São Paulo, 01246-903 São Paulo, Brazil.
12
Institute for Clinical Radiology, Ludwig Maximilians University Munich, 81377 Munich, Germany.
13
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.
14
Leibniz-Institut für Analytische Wissenschaften (ISAS), 44227 Dortmund, Germany.
15
Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Saint Mary's Hospital, Oxford Road, Manchester M13 9WL, UK.
16
Institute of Pathology, Ludwig-Maximilians University Munich, 80337 Munich, Germany.
17
Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK.
18
Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
19
Friedrich-Baur-Institute, Department of Neurology, Ludwig Maximilians University Munich, 80336 Munich, Germany. Electronic address: jan.senderek@med.uni-muenchen.de.

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.

KEYWORDS:

INPP5K; cognitive impairment; congenital muscular dystrophy; early cataracts; phosphoinositide phosphatase

PMID:
28190456
PMCID:
PMC5339217
DOI:
10.1016/j.ajhg.2017.01.024
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center