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 accompanied by a variety of brain and eye malformations. It represents the most severe clinical phenotype in a spectrum of alpha-dystroglycan posttranslational processing abnormalities, which share a defect in laminin binding glycan synthesis1. Although six WWS causing genes have been described, only half of all patients can currently be diagnosed genetically2. A cell fusion complementation assay using fibroblasts from undiagnosed WWS individuals identified five novel complementation groups. Further evaluation of one group by linkage analysis and targeted sequencing identified recessive mutations in the isoprenoid synthase domain containing (ISPD) gene. Confirmation of the pathogenicity of the identified ISPD mutations was demonstrated 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 novel mechanism for WWS pathophysiology.

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle

“…The extracellular matrix receptor function of α-DG is impaired when either DAG1 is itself mutated (limb-girdle muscular dystrophy type 2P) (10,16,17) or genes that encode putative or known glycosyltransferases that act on α-DG are mutated (Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, or limb-girdle muscular dystrophy) (12,18,19). Sarcolemmal expression of α-DG, sarcospan, and the sarcoglycan complex is reduced in patients with distinct sarcoglycan mutations (limb-girdle muscular dystrophy type 2C-F) (3)(4)(5)20).…”

Gènes impliqués dans les alpha-dystroglycanopathies

“…Récemment, il a été montré que la synthèse du CDP-Ribitol ( Figure 1E), substrat pour FKRP et FKTN, est catalysée par une enzyme codée par le gène ISPD [9,45]. Ce gène avait été identifié par différentes équipes dès 2013, à partir d'études sur des patients LISII [28] ou WWS [46,47]. Des mutations du gène ISPD avaient ensuite également été identifiées chez des patients avec une clinique moins sévère, parfois sans atteinte neurologique, à l'image de ce qui est constaté pour les patients FKRP.…”

The O-Mannosylation Pathway: Glycosyltransferases and Proteins Implicated in Congenital Muscular Dystrophy

“…ISPD is not predicted to be a glycosyltransferase, yet mutations in this protein cause Walker-Warburg syndrome with clear loss of ␣-dystroglycan functional glycosylation (51,52). This enzyme has high similarity to an enzyme in the non-mevalonate pathway for isoprenoid synthesis (53).…”

“…However, mammals are thought to use only the mevalonate pathway, and several other enzymes in the bacterial non-mevalonate pathway are not obviously conserved in higher animals (53). Thus, the role for this putative enzyme remains unclear, although it clearly impacts the ability of POMT1/2 to transfer O-mannose (52). Does the defect in ISPD affect other types of glycosylation that depend on dolichol-linked sugars?…”