Brain Advance Access originally published online on March 2, 2007
Brain 2007 130(6):1477-1484; doi:10.1093/brain/awm006
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Zaspopathy in a large classic late-onset distal myopathy family
1Department of Neurology, University of Rochester Medical Center, Rochester, NY, 7Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, MN, USA, 2Folkhalsan Institute of Genetics and Department of Medical Genetics, 8Neuroscience Program and Department of Pathology, University of Helsinki, Helsinki, 3Department of Pathology, University of Turku and Turku University Hospital, Turku, 9Department of Neurology, Vasa Central Hospital, Vasa, 10Department of Neurology, Tampere University Hospital, Tampere, Finland, 4Muscle Molecular Biology Unit, International Centre of Genetic Engineering and Biotechnology, Trieste, Italy, 5Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, Paris and 6Généthon, CNRS-UMR8115, Évry, France
Corresponding to: Bjarne Udd, Folkhalsan Institute of Genetics and Department of Medical Genetics, P.O.B. 63, FIN-00014, University of Helsinki, Helsinki, Finland. E-mail: bjarne.udd{at}netikka.fi
Distal myopathies have been associated with mutations in titin, dysferlin, GNE, desmin and myosin. Of these, only titin mutations were previously known to cause dominant late-onset distal myopathy. Recent findings, however, have indicated that patients affected with myofibrillar myopathy have a more distal than proximal muscle phenotype and a proportion of these may have mutations in myotilin, ZASP or filamin C, besides previously known desmin and 
B-crystallin. Here we report that the disorder in one of the well-characterized autosomal dominant distal myopathy families, the Markesbery et al. family, first reported in 1974, is caused by ZASP mutation A165V. Previous linkage to the titin locus 2q31 proved incorrect. ZASP expression by immunoblotting shows normal presence of the main 32 and 78 kDa bands and immunohistochemistry in patients reveals normal Z-disc localization except for moderate accumulations together with myotilin, desmin B-crystallin and -actinin. Muscle imaging reveals involvement in both the posterior and anterior compartments of the lower leg and considerable affection of proximal leg muscles at later stages. Haplotype studies in this family and in five other unrelated families with European ancestry carrying the identical A165V mutation share common markers at the locus suggesting the existence of a founder mutation.
Key Words: myofibrillar myopathy; distal myopathy; ZASP
Abbreviations: DCM, dilated cardiomyopathy; ECL, enhanced chemiluminescence; HRP, horseradish peroxidase; MFM, myofibrillar myopathies; ZASP, Z-band alternatively spliced PDZ-motif containing protein; ZM, zasp-like motif
Received December 7, 2006. Revised January 2, 2007. Accepted January 5, 2007.
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