title: Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy.
abstract: Congenital muscular dystrophies display a wide phenotypic and genetic heterogeneity. The combination of clinical, biochemical, and molecular genetic findings must be considered to obtain the precise diagnosis and provide appropriate genetic counselling. Here we report five individuals from four families presenting with variable clinical features including muscular dystrophy with a reduction in dystroglycan glycosylation, short stature, intellectual disability, and cataracts, overlapping both the dystroglycanopathies and Marinesco-Sjögren syndrome. Whole-exome sequencing revealed homozygous missense and compound heterozygous mutations in INPP5K in the affected members of each family. INPP5K encodes the inositol polyphosphate-5-phosphatase K, also known as SKIP (skeletal muscle and kidney enriched inositol phosphatase), which is highly expressed in the brain and muscle. INPP5K localizes to both the endoplasmic reticulum and to actin ruffles in the cytoplasm. It has been shown to regulate myoblast differentiation and has also been implicated in protein processing through its interaction with the ER chaperone HSPA5/BiP. We show that morpholino-mediated inpp5k loss of function in the zebrafish results in shortened body axis, microphthalmia with disorganized lens, microcephaly, reduced touch-evoked motility, and highly disorganized myofibers. Altogether these data demonstrate that mutations in INPP5K cause a congenital muscular dystrophy syndrome with short stature, cataracts, and intellectual disability.
authors.affiliation: Cardiovascular and Cell Sciences Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Daniel P S
authors.initials: DPS
authors.lastname: Osborn
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Science, Washington, DC 20037, USA.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Pond
authors.affiliation: Department of Genetics, Shahid Chamran University of Ahvaz, Ahvaz 6135783151, Iran; Narges Medical Genetics and Prenatal Diagnosis Laboratory, East Mihan Ave., Kianpars, Ahvaz 6155689467, Iran.
authors.forename: Neda
authors.initials: N
authors.lastname: Mazaheri
authors.affiliation: Cardiovascular and Cell Sciences Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Dejardin
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Munn
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Science, Washington, DC 20037, USA.
authors.forename: Khaloob
authors.initials: K
authors.lastname: Mushref
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Science, Washington, DC 20037, USA.
authors.forename: Edmund S
authors.initials: ES
authors.lastname: Cauley
authors.affiliation: Pediatric Neurology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, 20133 Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
authors.affiliation: Pediatric Neurology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, 20133 Milan, Italy; Division of Neuromuscular Diseases and Neuroimmunology, Fondazione IRCCS Istituto Neurologico C. Besta, 20126 Milan, Italy.
authors.forename: Maria Barbara
authors.initials: MB
authors.lastname: Pasanisi
authors.affiliation: Department of Pediatrics, Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR 72202, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Sellars
authors.affiliation: Program in Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: R Sean
authors.initials: RS
authors.lastname: Hill
authors.affiliation: Program in Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Partlow
authors.affiliation: GeneDX, Gaithersburg, MD 20877, USA.
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Willaert
authors.affiliation: Cardiovascular and Cell Sciences Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: Jaipreet
authors.initials: J
authors.lastname: Bharj
authors.affiliation: Department of Paediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6163764648, Iran.
authors.forename: Reza Azizi
authors.initials: RA
authors.lastname: Malamiri
authors.affiliation: Department of Genetics, Shahid Chamran University of Ahvaz, Ahvaz 6135783151, Iran; Narges Medical Genetics and Prenatal Diagnosis Laboratory, East Mihan Ave., Kianpars, Ahvaz 6155689467, Iran.
authors.forename: Hamid
authors.initials: H
authors.lastname: Galehdari
authors.affiliation: Narges Medical Genetics and Prenatal Diagnosis Laboratory, East Mihan Ave., Kianpars, Ahvaz 6155689467, Iran; Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur, University of Medical Sciences, Ahvaz 6135715794, Iran.
authors.forename: Gholamreza
authors.initials: G
authors.lastname: Shariati
authors.affiliation: Cardiovascular and Cell Sciences Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK; University of Exeter Medical School, RILD Wellcome Wolfson Centre, Royal Devon & Exeter NHS Foundation Trust, Exeter EX1 2LU, UK.
authors.forename: Reza
authors.initials: R
authors.lastname: Maroofian
authors.affiliation: Division of Neuromuscular Diseases and Neuroimmunology, Fondazione IRCCS Istituto Neurologico C. Besta, 20126 Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.affiliation: Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Swan
authors.affiliation: NIHR GOSH Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.affiliation: NIHR GOSH Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: Conti
authors.affiliation: Cardiovascular and Cell Sciences Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK. Electronic address: yjamshid@sgul.ac.uk.
authors.forename: Yalda
authors.initials: Y
authors.lastname: Jamshidi
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Science, Washington, DC 20037, USA. Electronic address: cmanzini@gwu.edu.
authors.forename: M Chiara
authors.initials: MC
authors.lastname: Manzini
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism; D002648:Child; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D055106:Genome-Wide Association Study; D006031:Glycosylation; D006130:Growth Disorders / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D013132:Spinocerebellar Degenerations / Q000235:genetics*; D055815:Young Adult; D015027:Zebrafish / Q000235:genetics
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D049030:Dystroglycans; C471548:SKIP enzyme, human; D010744:Phosphoric Monoester Hydrolases
keywords: INPP5K; Marinesco-Sjögren syndrome; SKIP; cataracts; dystroglycanopathy; inositol phosphatase; intellectual disability; muscular dystrophy