Article

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

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.

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Available from: Tobias Willer, Dec 17, 2014
    • "Although in a previous study POMT activity was found to be comparable between ISPD-deficient fibroblasts (30–150 pmol/g/h) and POMT1-deficient fibroblasts ($100 pmol/g/h) (Willer et al., 2012), our data indicate that hISPD acts independently from POMT activity in a-DG O-mannosylation. This discrepancy might be explained by the high residual POMT activity in POMT1-deficient fibroblasts (Willer et al., 2012) compared with other reports on POMT1-and POMT2-deficient patients (Lommel et al., 2010; Manya et al., 2004). "
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    ABSTRACT: A unique, unsolved O-mannosyl glycan on α-dystroglycan is essential for its interaction with protein ligands in the extracellular matrix. Defective O-mannosylation leads to a group of muscular dystrophies, called dystroglycanopathies. Mutations in isoprenoid synthase domain containing (ISPD) represent the second most common cause of these disorders, however, its molecular function remains uncharacterized. The human ISPD (hISPD) crystal structure showed a canonical N-terminal cytidyltransferase domain linked to a C-terminal domain that is absent in cytidyltransferase homologs. Functional studies demonstrated cytosolic localization of hISPD, and cytidyltransferase activity toward pentose phosphates, including ribulose 5-phosphate, ribose 5-phosphate, and ribitol 5-phosphate. Identity of the CDP sugars was confirmed by liquid chromatography quadrupole time-of-flight mass spectrometry and two-dimensional nuclear magnetic resonance spectroscopy. Our combined results indicate that hISPD is a cytidyltransferase, suggesting the presence of a novel human nucleotide sugar essential for functional α-dystroglycan O-mannosylation in muscle and brain. Thereby, ISPD deficiency can be added to the growing list of tertiary dystroglycanopathies. Guided by X-ray crystallography and biochemical studies in ISPD knockout and overexpressing cell models, we implicated human ISPD in the synthesis of a novel human nucleotide sugar required for dystroglycan O-mannosylation in muscle and brain.
    No preview · Article · Dec 2015
    • "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]. "

    No preview · Article · Oct 2015 · Neuromuscular Disorders
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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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    ABSTRACT: Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of muscle disorders, which first affect the voluntary muscles of the hip and shoulder areas. The definition is highly descriptive and less ambiguous by exclusion: non-Xlinked, non-FSH, non-myotonic, non-distal, nonsyndromic, and non-congenital. At present, the genetic classification is becoming too complex, since the acronym LGMD has also been used for a number of other myopathic disorders with overlapping phenotypes. Today, the list of genes to be screened is too large for the gene-by-gene approach and it is well suited for targeted next generation sequencing (NGS) panels that should include any gene that has been so far associated with a clinical picture of LGMD. The present review has the aim of recapitulating the genetic basis of LGMD ordering and of proposing a nomenclature for the orphan forms. This is useful given the pace of new discoveries. Thity-one loci have been identified so far, eight autosomal dominant and 23 autosomal recessive. The dominant forms (LGMD1) are: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin 3), LGMD1D (DNAJB6), LGMD1E (desmin), LGMD1F (transportin 3), LGMD1G (HNRPDL), LGMD1H (chr. 3). The autosomal recessive forms (LGMD2) are: LGMD2A (calpain 3), LGMD2B (dysferlin), LGMD2C (γ sarcoglycan), LGMD2D (α sarcoglycan), LGMD2E (β sarcoglycan), LGMD2F (δ sarcoglycan), LGMD2G (telethonin), LGMD2H (TRIM32), LGMD2I (FKRP), LGMD2J (titin), LGMD2K (POMT1), LGMD2L (anoctamin 5), LGMD2M (fukutin), LGMD2N (POMT2), LGMD2O (POMTnG1), LGMD2P (dystroglycan), LGMD2Q (plectin), LGMD2R (desmin), LGMD2S (TRAPPC11), LGMD2T (GMPPB), LGMD2U (ISPD), LGMD2V (Glucosidase, alpha ), LGMD2W (PINCH2).
    Full-text · Article · May 2014 · Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases
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