title: ISPD loss-of-function mutations disrupt dystroglycan  O-mannosylation and cause Walker-Warburg syndrome.
abstract: 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.
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Willer
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.forename: Mark
authors.initials: M
authors.lastname: Lommel
authors.forename: Takako
authors.initials: T
authors.lastname: Yoshida-Moriguchi
authors.forename: Daniel Beltran Valero
authors.initials: DB
authors.lastname: de Bernabe
authors.forename: David
authors.initials: D
authors.lastname: Venzke
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.forename: Harry
authors.initials: H
authors.lastname: Schachter
authors.forename: Jiri
authors.initials: J
authors.lastname: Vajsar
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Loder
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Winder
authors.forename: Sabine
authors.initials: S
authors.lastname: Strahl
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Mathews
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
mesh_terms: D002478:Cells, Cultured; D049030:Dystroglycans / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005816:Genetic Complementation Test; D006031:Glycosylation; D006801:Humans; D007223:Infant; D007797:Laminin / Q000378:metabolism; D008358:Mannose / Q000378:metabolism*; D008364:Mannosyltransferases / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D009713:Nucleotidyltransferases / Q000235:genetics*; D011134:Polysaccharides / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism; D058494:Walker-Warburg Syndrome / Q000235:genetics*
chemical_list: D007797:Laminin; D011134:Polysaccharides; D049030:Dystroglycans; D008364:Mannosyltransferases; C082696:protein O-mannosyltransferase; D009713:Nucleotidyltransferases; C573136:CRPPA protein, human; D008358:Mannose