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POMK mutation in a family with congenital muscular dystrophy with merosin deficiency, hypomyelination, mild hearing deficit and intellectual disability
  1. Anja von Renesse1,2,
  2. Mina V Petkova1,2,
  3. Susanne Lützkendorf1,2,
  4. Jan Heinemeyer1,3,
  5. Esther Gill1,2,
  6. Christoph Hübner1,
  7. Arpad von Moers4,
  8. Werner Stenzel5,
  9. Markus Schuelke1,2
  1. 1Department of Neuropediatrics, Charité—Universitätsmedizin Berlin, Berlin, Germany
  2. 2NeuroCure Clinical Research Center, Charité—Universitätsmedizin Berlin, Berlin, Germany;
  3. 3Division Neuropediatrics, Children's Hospital Altona, Hamburg, Germany
  4. 4Department of Pediatrics, DRK Kliniken Berlin Westend, Berlin, Germany
  5. 5Department of Neuropathology, Charité—Universitätsmedizin Berlin, Berlin, Germany.
  1. Correspondence to Professor Markus Schuelke, Department of Neuropediatrics, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin D-13353, Germany; markus.schuelke{at}


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.

  • Muscle disease
  • Genome-wide
  • Molecular genetics
  • Clinical genetics

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