title: POMK mutation in a family with congenital muscular dystrophy with merosin deficiency, hypomyelination, mild hearing deficit and intellectual disability.
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.
authors.affiliation: Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: von Renesse
authors.forename: Mina V
authors.initials: MV
authors.lastname: Petkova
authors.forename: Susanne
authors.initials: S
authors.lastname: Lützkendorf
authors.forename: Jan
authors.initials: J
authors.lastname: Heinemeyer
authors.forename: Esther
authors.initials: E
authors.lastname: Gill
authors.forename: Christoph
authors.initials: C
authors.lastname: Hübner
authors.forename: Arpad
authors.initials: A
authors.lastname: von Moers
authors.forename: Werner
authors.initials: W
authors.lastname: Stenzel
authors.forename: Markus
authors.initials: M
authors.lastname: Schuelke
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D034381:Hearing Loss / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D007797:Laminin / Q000172:deficiency*; D008297:Male; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology; D009136:Muscular Dystrophies / Q000150:complications / Q000151:congenital* / Q000201:enzymology / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009186:Myelin Sheath / Q000473:pathology*; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics*; D055815:Young Adult
chemical_list: D007797:Laminin; C583116:POMK protein, human; D011494:Protein Kinases
keywords: Clinical genetics; Genome-wide; Molecular genetics; Muscle disease