Natural history of dilated cardiomyopathy due to lamin A/C gene mutations
Matthew R. G. Taylor, MD*,
Pamela R. Fain, PhD*  ,
Gianfranco Sinagra, MD, FESC ,
Misi L. Robinson||,
Alastair D. Robertson, PhD*,
Elisa Carniel, MD,
Andrea Di Lenarda, MD, FESC,
Teresa J. Bohlmeyer, MD*,
Debra A. Ferguson, MS*,
Gary L. Brodsky, PhD*,
Mark M. Boucek, MD*¶,
Jean Lascor, MS¶,
Andrew C. Moss, BA*,
Wai-Lun P. Li, BS*,
Gary L. Stetler, PhD,
Francesco Muntoni, MD, FRCPCH#,
Michael R. Bristow, MD, PhD, FACC*,
Luisa Mestroni, MD, FACC, FESC*,* Familial Dilated Cardiomyopathy Registry Research Group
* University of Colorado Cardiovascular Institute, Denver, Colorado USA
Human Medical Genetics Program, University of Colorado Health Sciences Center, Denver, Colorado USA
Department of Internal Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA
Division of Cardiology, Ospedale Maggiore and University of Trieste, Trieste, Italy
|| Transgenomic, Inc., Omaha, Nebraska, USA
¶ Division of Cardiology, The Children’s Hospital, Denver, Colorado, USA
# Neuromuscular Unit, Department of Pediatrics and Neonatal Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom
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Figure 1 The denaturing high performance liquid chromatography elution profiles for lamin A/C gene (LMNA) mutations detected in three families with dilated cardiomyopathy. (Top) Pedigree of the families: individuals are indicated by generation and pedigree number. Affected status is indicated by filled symbols, unaffected by clear symbols. The (+) and (–) symbols indicate the presence of the mutant allele and the wild type, respectively. (Middle) Elution profiles for the wild-type and patients carrying the LMNA mutations (G266T: III-2; 959delT: II-1; G1130A: II-2; C1718T: II-2). (Bottom) The direct sequencing results illustrate the corresponding nucleotide substitutions (reverse sequence shown for G1130A mutation).
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Figure 2 Structure of lamin A/C gene (LMNA) and of the lamin A/C protein. LMNA encodes lamin A (664 amino acids) and lamin C (572 amino acids) by alternative splicing in exon 10. The region common to both lamins includes the globular head, the  -helical domain (coils 1a, 1b, and 2, separated by linkers depicted as diagonal stripes), and part of the tail (566 amino acids). The mutations identified in patients with DCM, the corresponding nucleotide, and their position on the protein are indicated (star = splice site mutation).
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Figure 3 Amino acid sequences alignment for lamin proteins from various species. The conservation of the residues corresponding to the R89L, R377H, and S573L mutations is shown. The corresponding GenBank accession numbers are listed in the column at far right.
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Figure 4 Skeletal muscle biopsy in dilated cardiomyopathy due to laminopathy. (A) Family MDDC1, Patient III-4 (hematoxylin-eosin, 40x), and (B) family DNFDC33, Patient II-2 (trichrome, 40x). Vastus lateralis muscle biopsies showing variability in fiber size, some angulated fibers, and several internal nuclei.
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Figure 5 Kaplan-Meier cumulative survival curves for (A) cardiovascular death, (B) cardiovascular death or transplant, and (C) cardiovascular death, transplant, or major cardiac events in 105 patients with dilated cardiomyopathy, carriers of lamin A/C gene mutations (dashed lines), and non-carriers (solid lines). P values are derived by Cox regression.
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