title: POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome.
abstract: BACKGROUND
  Walker-Warburg syndrome (WWS) is an autosomal recessive condition characterised by congenital muscular dystrophy, structural brain defects, and eye malformations. Typical brain abnormalities are hydrocephalus, lissencephaly, agenesis of the corpus callosum, fusion of the hemispheres, cerebellar hypoplasia, and neuronal overmigration, which causes a cobblestone cortex. Ocular abnormalities include cataract, microphthalmia, buphthalmos, and Peters anomaly. WWS patients show defective O-glycosylation of alpha-dystroglycan (alpha-DG), which plays a key role in bridging the cytoskeleton of muscle and CNS cells with extracellular matrix proteins, important for muscle integrity and neuronal migration. In 20% of the WWS patients, hypoglycosylation results from mutations in either the protein O-mannosyltransferase 1 (POMT1), fukutin, or fukutin related protein (FKRP) genes. The other genes for this highly heterogeneous disorder remain to be identified.
  
  
  OBJECTIVE
  To look for mutations in POMT2 as a cause of WWS, as both POMT1 and POMT2 are required to achieve protein O-mannosyltransferase activity.
  
  
  METHODS
  A candidate gene approach combined with homozygosity mapping.
  
  
  RESULTS
  Homozygosity was found for the POMT2 locus at 14q24.3 in four of 11 consanguineous WWS families. Homozygous POMT2 mutations were present in two of these families as well as in one patient from another cohort of six WWS families. Immunohistochemistry in muscle showed severely reduced levels of glycosylated alpha-DG, which is consistent with the postulated role for POMT2 in the O-mannosylation pathway.
  
  
  CONCLUSIONS
  A fourth causative gene for WWS was uncovered. These genes account for approximately one third of the WWS cases. Several more genes are anticipated, which are likely to play a role in glycosylation of alpha-DG.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van Reeuwijk
authors.forename: M
authors.initials: M
authors.lastname: Janssen
authors.forename: C
authors.initials: C
authors.lastname: van den Elzen
authors.forename: D
authors.initials: D
authors.lastname: Beltran-Valero de Bernabé
authors.forename: P
authors.initials: P
authors.lastname: Sabatelli
authors.forename: L
authors.initials: L
authors.lastname: Merlini
authors.forename: M
authors.initials: M
authors.lastname: Boon
authors.forename: H
authors.initials: H
authors.lastname: Scheffer
authors.forename: M
authors.initials: M
authors.lastname: Brockington
authors.forename: F
authors.initials: F
authors.lastname: Muntoni
authors.forename: M A
authors.initials: MA
authors.lastname: Huynen
authors.forename: A
authors.initials: A
authors.lastname: Verrips
authors.forename: C A
authors.initials: CA
authors.lastname: Walsh
authors.forename: P G
authors.initials: PG
authors.lastname: Barth
authors.forename: H G
authors.initials: HG
authors.lastname: Brunner
authors.forename: H
authors.initials: H
authors.lastname: van Bokhoven
mesh_terms: D001921:Brain / Q000378:metabolism / Q000473:pathology; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D049030:Dystroglycans / Q000235:genetics*; D005192:Family Health; D005260:Female; D006031:Glycosylation; D006720:Homozygote; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008364:Mannosyltransferases / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D017354:Point Mutation; D013577:Syndrome
chemical_list: D017931:DNA Primers; D049030:Dystroglycans; D008364:Mannosyltransferases; C082696:protein O-mannosyltransferase