Limb-Girdle Muscular Dystrophy with α-Dystroglycan Deficiency and Mutations in the ISPD GENE.

From the Don Carlo Gnocchi Onlus Foundation (G.T.), Italy
Neurology (Impact Factor: 8.29). 02/2013; 80(10). DOI: 10.1212/WNL.0b013e3182840cbc
Source: PubMed


Defects in the posttranslational modification of α-dystroglycan (α-DG) have been implicated in clinically distinct dystroglycanopathies that present as congenital muscular dystrophies with multisystem involvement, limb-girdle muscular dystrophies (LGMDs), or a spectrum of intermediate phenotypes.(1,2) Recently, mutations in ISPD, encoding the isoprenoid synthase domain containing protein, have been described in Walker-Warburg syndrome and muscle-eye-brain disease, 2 typical dystroglycanopathies.(3,4).

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    ABSTRACT: Walker-Warburg syndrome (WWS) is a severe muscular dystrophy with eye and brain malformations. On a molecular level, WWS is a disorder of the O-linked glycosylation of α-dystroglycan and therefore referred to as one of the dystroglycanopathies. The disease family of muscular dystrophy-dystroglycanopathy (MDDG) contains a spectrum of severe to mild disorders, designated as MDDG type A to C. WWS, as the most severe manifestation, corresponds to MDDG type A. Defects in the genes POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE, GTDC2, G3GALNT2, GMPPB, B3GNT1, TMEM5 and COL4A1 and ISPD have been described as causal for several types of MDDG including WWS, but can only be confirmed in about 60-70% of the clinically diagnosed individuals. The proteins encoded by these genes are involved in the posttranslational modification of α-dystroglycan. Mutations in POMT1, POMT2, POMGNT1, FKTN, FKRP, LARGE, GMPPB, TMEM5 and COL4A1 and ISPD lead to a wide spectrum of phenotypes of congenital muscular dystrophies with or without eye and brain abnormalities. Patients with WWS frequently demonstrate a complete lack of psychomotor development, severe eye malformations, cobblestone lissencephaly and a hypoplastic cerebellum and brainstem, seizures, hydrocephalus and poor prognosis. Here, we present a boy with WWS who showed compound heterozygous changes in ISPD and discuss the clinical and radiological phenotype and the molecular genetic findings, including a novel pathogenic mutation in ISPD.
    No preview · Article · Oct 2013 · European journal of medical genetics
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    ABSTRACT: The Third International Workshop for Glycosylation Defects in Muscular Dystrophies took place on April 18(th) and 19(th) , 2013 in Charlotte, North Carolina, USA. The event was sponsored by the Carolinas Healthcare Foundation, the Muscular Dystrophy Association (MDA), funds raised by "Jeans, Genes and Geniuses" organized by Jane and Luther Lockwood as well as generous support by the McColl and Lockwood families. This workshop focused on the topics of Glycosylation, AAV Therapy and Drug Discover, Genetic Diagnosis and Clinical Management of dystroglycanopathies. Top scientists and clinicians were brought in from the US, UK and Japan to speak on these topics over a period of two days. This workshop provided a distinct opportunity to discuss the significant advances that have been made over the past 2 years in the field of dystroglycanopathies with a focus on identifying targets for therapies as well as facilitating collaboration.
    No preview · Article · Jan 2014 · Brain Pathology
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    ABSTRACT: The mammalian O-mannosylation pathway for protein post-translational modification is intricately involved in modulating cell-matrix interactions in the musculature and nervous system. Defects in enzymes of this biosynthetic pathway are causative for multiple forms of congenital muscular dystophy. The application of advanced genetic and biochemical technologies has resulted in remarkable progress in this field over the past few years culminating with the publication of three landmark papers in 2013 alone. In this review, we will highlight recent progress focusing on the dramatic expansion in the set of genes known to be involved in O-mannosylation and disease processes, the concurrent acceleration in the rate of O-mannosylation pathway protein functional assignments, the tremendous increase in the number of proteins now known to be modified by O-mannosylation, and the recent progress in protein O-mannose glycan quantification and site assignment. Also, we attempt to highlight key outstanding questions raised by this abundance of new information.
    Preview · Article · May 2014 · Biochemistry
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