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Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease

Eloisa Arbustini, MD^*,*, Andrea Pilotto, TD^*, Alessandra Repetto, MD, Maurizia Grasso, PhD^*, Andrea Negri, TD^*, Marta Diegoli, PhD^*, Carlo Campana, MD, Laura Scelsi, MD, Elisa Baldini, MD, Antonello Gavazzi, MD and Luigi Tavazzi, MD

^* Molecular Diagnostic Division, IRCCS Policlinico San Matteo, Pavia, Italy
Cardiology Division, IRCCS Policlinico San Matteo, Pavia, Italy
Cardiology Division, Ospedali Riuniti, Bergamo, Italy

View larger version (41K): [in a new window]   Figure 1 Localization of published lamin A/C (LMNA) mutations and corresponding phenotypes; the gray square contains the mutations found in this study. A-V = atrioventricular; DCM = dilated cardiomyopathy; EDMD = Emery-Dreifuss muscular dystrophy; FPL = familial partial lipodystrophy; LGMD = limb girdle muscular dystrophy.

View larger version (37K): [in a new window]   Figure 2 1) Family A: mutation E111X; 2) Family B: mutation K97E; 3) Family C: CTGC insertion at 2,869 of the cDNA; 4) Family D: mutation R190W; 5) Family E: mutation E317K. Filled symbols = patients; open symbols = non-affected subjects; question marks within symbols = non-proven affected subjects. Small squares within symbols = atrioventricular block (upper left), left ventricular dilation (upper right). Diagonal lines = death. The probands are indicated by arrows. The presence (+) or absence (–) of the mutation is indicated for the genetically tested family members. Chromatograms below each pedigree demonstrate the heterozygous mutations.

View larger version (173K): [in a new window]   Figure 3 Electron micrographs showing nuclear membrane damage (arrow) (a), bleb formation (arrow) (b) and c) and nuclear pore clustering (arrow) (d) in cardiac myocytes from myocardial samples of patients A-II-1 (a), B-III-1 (b), C-II-2 (c) and D-II-1 (d) (uranyl-acetate, lead citrate). Bar scales = 0.6 mµ.

View larger version (212K): [in a new window]   Figure 4 Lamin A/C immunostain (a, c, e) and corresponding DAPI nuclear stain (b, d, f). (a, b) Normal heart sample. (c, d) Control dilated cardiomyopathy without (LMNA) mutation; all myocyte and interstitial-vascular nuclei are immunostained by the anti-LMNA antibody. (e, f) Endomyocardial biopsy from patient A-II-1; note the absence of LMNA immunostain in some myocyte nuclei and positive interstitial-vascular cell nuclei (Avidin-Biotin Complex, DAPI nuclear stain; a and b, 40x; c to f, 110x).

View larger version (99K): [in a new window]   Figure 5 Atrioventricular junction of patients A-II-1 and B-III-1: fibrosclerosis and fibrofatty degeneration (Movat Pentachrome stain, 10x).

View larger version (68K): [in a new window]   Figure 6 Western blot showing lamin A and lamin C bands and the additional 30 kDa immunoreacting band corresponding to an abnormal small peptide comprising the epitope recognized by the antibody. This band is identical in patients with different lamin A/C (LMNA) mutations (lane 2: A-II-1; lane 3: B-III-1; lane 5: A-II-2) but absent in normal controls (lane 1) and patients with dilated cardiomyopathy unrelated to LMNA defects (lane 4).