ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome

Department of Molecular Physiology and Biophysics, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USA.
Nature Genetics (Impact Factor: 29.35). 04/2012; 44(5):575-80. DOI: 10.1038/ng.2252
Source: PubMed


Walker-Warburg syndrome (WWS) is clinically defined as congenital muscular dystrophy that is accompanied by a variety of brain and eye malformations. It represents the most severe clinical phenotype in a spectrum of diseases associated with abnormal post-translational processing of a-dystroglycan that share a defect in laminin-binding glycan synthesis1. Although mutations in six genes have been identified as causes of WWS, only half of all individuals with the disease can currently be diagnosed on this basis2. A cell fusion complementation assay in fibroblasts from undiagnosed individuals with WWS was used to identify five new complementation groups. Further evaluation of one group by linkage analysis and targeted sequencing identified recessive mutations in the ISPD gene (encoding isoprenoid synthase domain containing). The pathogenicity of the identified ISPD mutations was shown by complementation of fibroblasts with wild-type ISPD. Finally, we show that recessive mutations in ISPD abolish the initial step in laminin-binding glycan synthesis by disrupting dystroglycan O-mannosylation. This establishes a new mechanism for WWS pathophysiology.

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Available from: Tobias Willer, Dec 17, 2014
    • "Muscle biopsy with immunostaining for glycosylated α-dystroglycan can suggest a dystroglycanopathy , or support the diagnosis when novel variants are identified . Unlike several other dystroglycanopathy genotypes [Willer et al., 2012], fibroblast cultures show only subtle, if any, defects in α-glycosylation status [Carss et al., 2013]. "

    Neuromuscular Disorders 10/2015; 25:S268-S269. DOI:10.1016/j.nmd.2015.06.300 · 2.64 Impact Factor
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    • "The ISPD gene spans 333kb at chromosome 7p21 and contains 10 exons. ISPD mutations disrupt dystroglycan mannosylation and cause of Walker- Warburg syndrome (82, 83). Mutations in ISPD as well as TMEM5 genes have been associated with severe cobblestone lissencephaly (84). "
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    • "Cultured fibroblasts derived from a skin biopsy of patient 2 were evaluated by western blotting as described by Willer et al. [19]. Alpha-dystroglycan expressed by this patient was reduced in molecular weight using a core peptide antibody. "
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