Further evidence of Fukutin mutations as a cause of childhood onset limb-girdle muscular dystrophy without mental retardation |
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| Authors: | Rebecca L Puckett Steven A Moore Thomas L Winder Tobias Willer Stephen G Romansky Kelly King Covault Kevin P Campbell Jose E Abdenur |
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| Institution: | 1. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;2. Sanford Children''s Health Research Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA;3. Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA;4. Department of Molecular and Cellular Biochemistry, Chandler Medical Center, College of Medicine, University of Kentucky, Lexington, KY, USA;5. Department of Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN, USA;6. Howard Hughes Medical Institute, Department of Molecular Physiology and Biophysics, Department of Neurology, Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA;1. Department of Neurology, Edith Wolfson Medical Center, Holon, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;2. Radcliffe Infirmary, Woodstock Road, Oxford, United Kingdom;3. National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, USA;4. Department of Molecular Genetic Laboratory, Edith Wolfson Medical Center, Holon, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;5. Folkhalsan Institute of Genetics, Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland;6. Neuromuscular Research Center, Tampere University and University Hospital, Tampere, Finland;7. Department of Neurology, Vasa Central Hospital, Vasa, Finland |
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| Abstract: | The dystroglycanopathies comprise a clinically and genetically heterogeneous group of muscular dystrophies characterized by deficient glycosylation of α-dystroglycan. Mutations in the fukutin (FKTN) gene have primarily been identified among patients with classic Fukuyama congenital muscular dystrophy (FCMD), a severe form of dystroglycanopathy characterized by CMD, cobblestone lissencephaly and ocular defects. We describe two brothers of Caucasian and Japanese ancestry with normal intelligence and limb-girdle muscular dystrophy (LGMD) due to compound heterozygous FKTN mutations. Muscle biopsy showed a dystrophy with selectively reduced α-dystroglycan glycoepitope immunostaining. Immunoblots revealed hypoglycosylation of α-dystroglycan and loss of laminin binding. FKTN gene sequencing identified two variants: c.340G>A and c.527T>C, predicting missense mutations p.A114T and p.F176S, respectively. Our results provide further evidence for ethnic and allelic heterogeneity and the presence of milder phenotypes in FKTN-dystroglycanopathy despite a substantial degree of α-dystroglycan hypoglycosylation in skeletal muscle. |
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