Further evidence of Fukutin mutations as a cause of childhood onset limb-girdle muscular dystrophy without mental retardation

• Published in: Neuromuscular disorders : NMD Vol. 19; no. 5; pp. 352 - 356
• Main Authors: Puckett, Rebecca L, Moore, Steven A, Winder, Thomas L, Willer, Tobias, Romansky, Stephen G, Covault, Kelly King, Campbell, Kevin P, Abdenur, Jose E
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 01.05.2009
• Subjects: Age of Onset; Asian - genetics; Child; Child, Preschool; DNA Mutational Analysis; Dystroglycanopathy; Dystroglycans - metabolism; Fukutin (FKTN); Fukuyama congenital muscular dystrophy (FCMD); Genetic Markers - genetics; Genetic Predisposition to Disease - ethnology; Genetic Predisposition to Disease - genetics; Genotype; Glycosylation; Humans; Intellectual Disability - genetics; Laminin - metabolism; Limb-girdle muscular dystrophy (LGMD); Male; Membrane Proteins - genetics; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiopathology; Muscular Dystrophies, Limb-Girdle - ethnology; Muscular Dystrophies, Limb-Girdle - genetics; Muscular Dystrophies, Limb-Girdle - metabolism; Mutation - genetics; Mutation, Missense - genetics; Neurology; White People; α-Dystroglycan; Dystroglycanopathy; Fukuyama congenital muscular dystrophy (FCMD); Fukutin (FKTN); Limb-girdle muscular dystrophy (LGMD); α-Dystroglycan
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2009.03.001

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.