TY - JOUR
T1 - Zaspopathy in a large classic late-onset distal myopathy family
AU - Griggs, R.
AU - Vihola, A.
AU - Hackman, P.
AU - Talvinen, K.
AU - Haravuori, H.
AU - Faulkner, G.
AU - Eymard, B.
AU - Richard, I.
AU - Selcen, D.
AU - Engel, A.
AU - Carpen, O.
AU - Udd, B.
N1 - Funding Information:
The SNP haplotyping was done by Charles Mein, Genome Centre, Barts and the London, Queen Mary’s School of Medicine and Dentistry, The John Vane Science Centre, London. Telethonin 1-167 antibody was a generous gift from Prof. M. Gautel, King’s College, London. G.F. was supported by Grant GGP04088 from the Telethon Foundation-Italy. O.C. was supported by Sigrid Juselius Foundation and Finnish Heart Association. B.U. was supported by Sigrid Juselius Foundation, the Folkhalsan Research Foundation and the Medical Research Fund of Vasa Central Hospital District.
PY - 2007/6
Y1 - 2007/6
N2 - 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 αB-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 αB-crystallin and α-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.
AB - 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 αB-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 αB-crystallin and α-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.
KW - Distal myopathy
KW - Myofibrillar myopathy
KW - ZASP
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U2 - 10.1093/brain/awm006
DO - 10.1093/brain/awm006
M3 - Article
C2 - 17337483
AN - SCOPUS:34250861423
SN - 0006-8950
VL - 130
SP - 1477
EP - 1484
JO - Brain
JF - Brain
IS - 6
ER -