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Marshfield, WI, United States

Willer T.,University of Iowa | Willer T.,Howard Hughes Medical Institute | Lee H.,University of California at Los Angeles | Lommel M.,University of Heidelberg | And 20 more authors.
Nature Genetics | Year: 2012

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 α-dystroglycan that share a defect in laminin-binding glycan synthesis. 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 basis. 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. © 2012 Nature America, Inc. All rights reserved. Source

Wu Y.,McMaster University | Weber J.L.,PreventionGenetics | Vladutiu G.D.,State University of New York at Buffalo | Tarnopolsky M.A.,McMaster University
Molecular Genetics and Metabolism | Year: 2011

McArdle disease is an autosomal recessive glycogenosis due to deficiency of the enzyme myophosphorylase. It results from homozygous or compound heterozygous mutations in the gene for this enzyme, PYGM. We report six novel mutations in the PYGM gene based upon sequencing data including three missense mutations (p.D51G, p.P398L, and p.N648Y), one nonsense mutation (p.Y75X), one frame-shift mutation (p.Y114SfsX181), and one amino acid deletion (p.Y53del) in six patients with McArdle disease. We also report on a Caucasian family that appeared to transmit McArdle disease in an autosomal dominant manner. In order to evaluate the potential pathogenicity of the sequence variants, we performed in silico analysis using PolyPhen-2 and SIFT BLink, along with species conservation analysis using UCSC Genome Browser. The above mutations were all predicted to be disease associated with high probability and with at least the same level of certainty as several confirmed mutations. The current data add to the list of pathogenic mutations in the PYGM gene associated with McArdle disease. © 2011 Elsevier Inc. Source

Brown L.M.,Florida College | Corrado M.M.,Florida College | van der Ende R.M.,University of Groningen | Derks T.G.J.,University of Groningen | And 8 more authors.
Journal of Inherited Metabolic Disease | Year: 2015

Introduction: Ketone formation is a normal response when hypoglycemia occurs. Since the majority of children with recurrent hypoglycemia cannot be diagnosed with a known endocrine or metabolic disorder on a critical sample, ketotic hypoglycemia has been described as the most common cause of low blood glucose concentrations in children. Critical samples, however, will miss the ketotic forms of glycogen storage disease (GSD), which present with elevated ketones, hypoglycemia, and normal hormonal concentrations. Results: A total of 164 children (96 boys, 68 girls) were enrolled in the study. Prediction of pathogenicity of DNA changes using computer modeling confirmed pathology in 20 individuals [four GSD 0, two GSD VI, 12 GSD IX alpha, one GSD IX beta, one GSD IX gamma] (12 %). Boys were most likely to have changes in the PHKA2 gene, consistent with GSD IX alpha, an X-linked disorder. Conclusions: Mutations in genes involved in glycogen synthesis and degradation were commonly found in children with idiopathic ketotic hypoglycemia. GSD IX is likely an unappreciated cause of ketotic hypoglycemia in children, while GSD 0 and VI are relatively uncommon. GSD IX alpha should particularly be considered in boys with unexplained hypoglycemia. © 2014, SSIEM. Source

Haws R.M.,Marshfield Clinic | Haws R.M.,Marshfield Clinic Research Foundation | Krentz A.D.,PreventionGenetics | Stankowski R.V.,Marshfield Clinic Research Foundation | And 2 more authors.
New Horizons in Translational Medicine | Year: 2015

Bardet-Biedl syndrome (BBS) is a rare, multisystemic, genetic disease and member of a group of disorders called ciliopathies. This syndrome provides a mechanistic model for ciliopathies that may also extend to common disorders with complex inheritance patterns, including diabetes mellitus and obesity. Dysregulation of signaling pathways altering the cellular response to the extracellular environment is primary to the ciliopathies and characteristic of BBS. As BBS-centered translational research moves forward, innovative advances provide opportunities to improve the care of individuals with BBS and other rare diseases as well as common related conditions. This review aims to highlight the current understanding of the mechanisms underlying BBS and opportunities for advancing the care of individuals with rare diseases. Focal points: •Bedside: understanding the multi-dimensional manifestations of ciliopathies, specifically Bardet-Biedl Syndrome (BBS) as a model ciliopathy, will accelerate research into therapeutic targets for ciliopathies, allowing for improved therapies for individuals with these debilitating disorders.•Benchside: elucidating the molecular mechanisms of BBS is likely to increase the chance of discovering novel therapeutic approaches that may be generalizable to other ciliopathies and perhaps to common related disorders, such as obesity and diabetes mellitus.•Industry: application of known drugs to new indications, or drug repositioning, and development of novel therapeutics, including gene therapies in BBS, may open new avenues for therapeutic discovery and development.•Community: rare diseases affect millions of individuals throughout the world with significant impact on quality of life and longevity. The development of multidisciplinary clinics for BBS and effective implementation of a rare disease registry provides a model for advancing the care of individuals with rare diseases.•Government and Regulatory Agencies: the importance of rare disease research and the impact of that research on common disorders should be supported with adequate funding and resources. Understanding the molecular pathways underlying ciliopathies, such as BBS, and advancement of translational medicine in ciliopathies will have far reaching societal benefits. © 2015 European Society for Translational Medicine. Source

Milone M.,Mayo Medical School | Liewluck T.,Mayo Medical School | Winder T.L.,PreventionGenetics | Pianosi P.T.,Mayo Medical School
Neuromuscular Disorders | Year: 2012

Anoctamin 5 and dysferlin mutations can result in myopathies with similar clinical phenotype. Amyloid deposits can occur in the muscle of patients with dysferlinopathy. We describe a 53-year-old woman with exercise intolerance since childhood, recurrent rhabdomyolysis and late-onset weakness. Muscle biopsy showed amyloid deposits within the blood vessel walls and around muscle fibers. Mutation analysis identified two pathogenic heterozygous mutations in anoctamin 5 and no mutations in dysferlin. To our knowledge this is the first report of muscle amyloidosis in anoctamin 5 muscular dystrophy. This finding suggests that patients with amyloid in muscle should be screened for anoctamin 5 muscular dystrophy. © 2011 Elsevier B.V. Source

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