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. Epub 2017 Feb 9.

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.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Animals
  • Brain / metabolism
  • Child
  • Disease Models, Animal
  • Dystroglycans / metabolism
  • Endoplasmic Reticulum / metabolism
  • Female
  • Genome-Wide Association Study
  • Glycosylation
  • Growth Disorders / genetics
  • Humans
  • Intellectual Disability / genetics
  • Male
  • Microcephaly / genetics
  • Muscle, Skeletal / metabolism
  • Muscular Dystrophies, Limb-Girdle / genetics*
  • Mutation
  • Pedigree
  • Phosphoric Monoester Hydrolases / genetics*
  • Spinocerebellar Degenerations / genetics*
  • Young Adult
  • Zebrafish / genetics

Substances

  • Dystroglycans
  • SKIP enzyme, human
  • Phosphoric Monoester Hydrolases