POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome

J van Reeuwijk, M Janssen, C van den Elzen, DBV de Bernabe, P Sabatelli, L Merlini, M Boon, H Scheffer, M Brockington, F Muntoni, MA Huynen, A Verrips, CA Walsh, PG Barth, HG Brunner, H van Bokhoven*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    328 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)907-912
    Number of pages6
    JournalJOURNAL OF MEDICAL GENETICS
    Volume42
    Issue number12
    DOIs
    Publication statusPublished - Dec-2005

    Keywords

    • CONGENITAL MUSCULAR-DYSTROPHIES
    • O-MANNOSYLTRANSFERASE ACTIVITY
    • EYE-BRAIN DISEASE
    • DEFECTIVE GLYCOSYLATION
    • GLYCOPROTEIN COMPLEX
    • MANNOSYL GLYCANS
    • GENE
    • DROSOPHILA
    • PHENOTYPE
    • FAMILY

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