Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy

Am J Hum Genet. 2017 Mar 2;100(3):537-545. doi: 10.1016/j.ajhg.2017.01.019.

Daniel P S Osborn ¹, Heather L Pond ², Neda Mazaheri ³, Jeremy Dejardin ¹, Christopher J Munn ⁴, Khaloob Mushref ², Edmund S Cauley ², Isabella Moroni ⁵, Maria Barbara Pasanisi ⁶, Elizabeth A Sellars ⁷, R Sean Hill ⁸, Jennifer N Partlow ⁸, Rebecca K Willaert ⁹, Jaipreet Bharj ¹, Reza Azizi Malamiri ¹⁰, Hamid Galehdari ³, Gholamreza Shariati ¹¹, Reza Maroofian ¹², Marina Mora ¹³, Laura E Swan ⁴, Thomas Voit ¹⁴, Francesco J Conti ¹⁴, Yalda Jamshidi ¹⁵, M Chiara Manzini ¹⁶

Affiliations

1 Cardiovascular and Cell Sciences Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.
2 Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Science, Washington, DC 20037, USA.
3 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.
4 Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.
5 Pediatric Neurology Unit, Fondazione IRCCS Istituto Neurologico C. Besta, 20133 Milan, Italy.
6 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.
7 Department of Pediatrics, Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR 72202, USA.
8 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.
9 GeneDX, Gaithersburg, MD 20877, USA.
10 Department of Paediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6163764648, Iran.
11 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.
12 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.
13 Division of Neuromuscular Diseases and Neuroimmunology, Fondazione IRCCS Istituto Neurologico C. Besta, 20126 Milan, Italy.
14 NIHR GOSH Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
15 Cardiovascular and Cell Sciences Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK. Electronic address: [email protected].
16 Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Science, Washington, DC 20037, USA. Electronic address: [email protected].

PMID: 28190459 DOI: 10.1016/j.ajhg.2017.01.019

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.

Keywords

INPP5K; Marinesco-Sjögren syndrome; SKIP; cataracts; dystroglycanopathy; inositol phosphatase; intellectual disability; muscular dystrophy.

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