title: Mutations in ZASP define a novel form of muscular dystrophy in humans.
abstract: Myofibrillar myopathy (MFM) is a morphologically distinct disorder in which disintegration of the Z-disk and then of the myofibrils is followed by abnormal accumulation of multiple proteins. Mutations in desmin, alphaB-crystallin, and myotilin, all Z-disk-related proteins, cause MFM in the minority of cases. ZASP (a Z-band alternatively spliced PDZ motif-containing protein) is another Z-disk-associated protein, and targeted deletion of ZASP in mouse causes skeletal and cardiac myopathy. We therefore searched for mutations in ZASP in 54 MFM patients and detected 3 heterozygous missense mutations in 11. Their age at onset was 44 to 73 years. Dominant inheritance was apparent in seven patients, cardiac involvement in three, and signs of peripheral neuropathy in five. Most patients had proximal and distal weakness, but in six, the weakness was greater distally than proximally. Ten carried either of two mutations in exon 6 (A147T and A165V) at or within a motif important in linking ZASP to the Z-disk; one carried a missense mutation in exon 9 (R268C). We conclude that (1) mutations in ZASP cause stereotyped MFM pathology; (2) cardiomyopathy, distal more than proximal weakness, and neuropathy are in the spectrum of zaspopathy; and (3) mutations in ZASP define a novel form of autosomal dominant muscular dystrophy in humans.
authors.affiliation: Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA. selcen.duygu@mayo.edu
authors.forename: Duygu
authors.initials: D
authors.lastname: Selcen
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Engel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D060588:LIM Domain Proteins; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009136:Muscular Dystrophies / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D016133:Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018398:Homeodomain Proteins; C120696:LDB3 protein, human; D060588:LIM Domain Proteins