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Mutations in ZASP define a novel form of muscular dystrophy in humans
Author(s) -
Selcen Duygu,
Engel Andrew G.
Publication year - 2005
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.20376
Subject(s) - missense mutation , myopathy , exon , desmin , muscular dystrophy , biology , weakness , mutation , genetics , cardiomyopathy , microbiology and biotechnology , medicine , anatomy , gene , immunohistochemistry , heart failure , vimentin
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, αB‐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. Ann Neurol 2005;57:269–276