POMK mutation in a family with congenital muscular dystrophy with merosin deficiency, hypomyelination, mild hearing deficit and intellectual disability

J Med Genet. 2014 Apr;51(4):275-82. doi: 10.1136/jmedgenet-2013-102236. Epub 2014 Feb 20.

Abstract

Background: Congenital muscular dystrophies (CMD) with hypoglycosylation of α-dystroglycan are clinically and genetically heterogeneous disorders that are often associated with brain malformations and eye defects. Presently, 16 proteins are known whose dysfunction impedes glycosylation of α-dystroglycan and leads to secondary dystroglycanopathy.

Objective: To identify the cause of CMD with secondary merosin deficiency, hypomyelination and intellectual disability in two siblings from a consanguineous family.

Methods: Autozygosity mapping followed by whole exome sequencing and immunochemistry were used to discover and verify a new genetic defect in two siblings with CMD.

Results: We identified a homozygous missense mutation (c.325C>T, p.Q109*) in protein O-mannosyl kinase (POMK) that encodes a glycosylation-specific kinase (SGK196) required for function of the dystroglycan complex. The protein was absent from skeletal muscle and skin fibroblasts of the patients. In patient muscle, β-dystroglycan was normally expressed at the sarcolemma, while α-dystroglycan failed to do so. Further, we detected co-localisation of POMK with desmin at the costameres in healthy muscle, and a substantial loss of desmin from the patient muscle.

Conclusions: Homozygous truncating mutations in POMK lead to CMD with secondary merosin deficiency, hypomyelination and intellectual disability. Loss of desmin suggests that failure of proper α-dystroglycan glycosylation impedes the binding to extracellular matrix proteins and also affects the cytoskeleton.

Keywords: Clinical genetics; Genome-wide; Molecular genetics; Muscle disease.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Base Sequence
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Family
  • Female
  • Hearing Loss / complications*
  • Hearing Loss / enzymology
  • Hearing Loss / genetics
  • Humans
  • Immunohistochemistry
  • Infant
  • Infant, Newborn
  • Intellectual Disability / complications*
  • Intellectual Disability / enzymology
  • Intellectual Disability / genetics
  • Laminin / deficiency*
  • Male
  • Molecular Sequence Data
  • Muscle, Skeletal / pathology
  • Muscular Dystrophies / complications
  • Muscular Dystrophies / congenital*
  • Muscular Dystrophies / enzymology
  • Muscular Dystrophies / genetics
  • Mutation / genetics*
  • Myelin Sheath / pathology*
  • Pedigree
  • Protein Kinases / genetics*
  • Young Adult

Substances

  • Laminin
  • POMK protein, human
  • Protein Kinases