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

Manuela Wiessner,Christopher J Munn,Maggie C Walter,Ranjith Viswanathan,Rahul Phadke,Rita Barresi,Osório Abath Neto,Laura E Swan,Volker Straub,Denisa Hathazi,René P Zahedi,Kate Bushby,Helen Kingston,Christian De Goede,Carsten G Bönnemann,Elizabeth Curtis,Francesco Muntoni,Hanns Lochmüller,Edmar Zanoteli,Dan Cox,Andreas Roos,Tim M Strom,Susanna Müller,Rolf Stucka,Helen Roper,Margherita Dell’Aica,Tamiris Borges Da Silva,Richard Charlton,Cristiane Araújo Martins Moreno,Tamieka Whyte,Jan Senderek,Simone Thiele,Caroline A Sewry ,Benedikt Schöser ,Juliane S Müller ,Umbertina Conti Reed ,C Marini Bettolo ,Birgit Ertl‐Wagner

doi:10.1016/j.ajhg.2017.01.024

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.

Highlights

Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous inherited disorders in which muscle weakness typically manifests at birth or in infancy.[1]
Most CMDs are inherited in an autosomal-recessive manner with the exception of de novo dominant inheritance in CMDs caused by LMNA mutations (MIM: 613205) and some cases of Ullrich CMD (MIM: 254090)
Variant calling, annotation, and filtering, we focused our analysis on non-synonymous homozygous variants located in the regions of interest on chr10q and chr17p and reduced potential diseasecausing variants to two changes on chr17p

Summary

Introduction

Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous inherited disorders in which muscle weakness typically manifests at birth or in infancy.[1] Delayed motor milestones, poor motor abilities, and joint or spinal rigidity are often the presenting features. Early cataracts, cerebellar atrophy, and variable intellectual disability suggest Marinesco-Sjogren syndrome (MSS [MIM: 248800]), which features characteristic ultrastructural muscle pathology (dense perinuclear membranous structures).[2,3,4] Most CMDs are inherited in an autosomal-recessive manner with the exception of de novo dominant inheritance in CMDs caused by LMNA mutations (MIM: 613205) and some cases of Ullrich CMD (MIM: 254090). Mutations can be identified in 25%–50% of CMD-affected case subjects,[6] suggesting the existence of unidentified additional genes harboring mutations causing CMD and underscoring the need for ongoing investigation into the genetic causes of CMD

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Results

Conclusion