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

Daniel P.S. Osborn, Heather L. Pond, Neda Mazaheri, Jeremy Dejardin, Christopher J. Munn, Khaloob Mushref, Edmund S. Cauley, Isabella Moroni, Maria Barbara Pasanisi, Elizabeth A. Sellars, R. Sean Hill, Jennifer N. Partlow, Rebecca K. Willaert, Jaipreet Bharj, Reza Azizi Malamiri, Hamid Galehdari, Gholamreza Shariati, Reza Maroofian, Marina Mora, Laura E. SwanThomas Voit, Francesco J. Conti, Yalda Jamshidi, M. Chiara Manzini

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)537-545
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number3
Publication statusPublished - Mar 2 2017


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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy'. Together they form a unique fingerprint.

Cite this