Background Inherited mutations cause approximately 35 percentof cases of dilated cardiomyopathy; however, few genes associatedwith this disease have been identified. Previously, we locateda gene defect that was responsible for autosomal dominant dilatedcardiomyopathy and conduction-system disease on chromosome 1p1–q21,where nuclear-envelope proteins lamin A and lamin C are encodedby the LMNA (lamin A/C) gene. Mutations in the head or taildomain of this gene cause Emery–Dreifuss muscular dystrophy,a childhood-onset disease characterized by joint contracturesand in some cases by abnormalities of cardiac conduction duringadulthood.
Methods We evaluated 11 families with autosomal dominant dilatedcardiomyopathy and conduction-system disease. Sequences of thelamin A/C exons were determined in probands from each family,and variants were confirmed by restriction-enzyme digestion.The genotypes of the family members were ascertained.
Results Five novel missense mutations were identified: fourin the -helical rod domain of the lamin A/C gene, and one inthe lamin C tail domain. Each mutation caused heritable, progressiveconduction-system disease (sinus bradycardia, atrioventricularconduction block, or atrial arrhythmias) and dilated cardiomyopathy.Heart failure and sudden death occurred frequently within thesefamilies. No family members with mutations had either jointcontractures or skeletal myopathy. Serum creatine kinase levelswere normal in family members with mutations of the lamin rodbut mildly elevated in some family members with a defect inthe tail domain of lamin C.
Conclusions Genetic defects in distinct domains of the nuclear-envelopeproteins lamin A and lamin C selectively cause dilated cardiomyopathywith conduction-system disease or autosomal dominant Emery–Dreifussmuscular dystrophy. Missense mutations in the rod domain ofthe lamin A/C gene provide a genetic cause for dilated cardiomyopathyand indicate that this intermediate filament protein has animportant role in cardiac conduction and contractility.
Dilated cardiomyopathy, a myocardial disorder characterizedby dilatation of the cardiac chambers and impaired systoliccontraction, is a major cause of congestive heart failure worldwide.Despite advances in therapy, mortality due to dilated cardiomyopathyremains high.1,2 Dilated cardiomyopathy can result from coronaryartery disease, myocarditis, or systemic diseases but can alsoresult from a primary (idiopathic) disorder of the myocyte'scontractile apparatus, cytoskeleton, or both.3 The cellularand molecular basis of primary dilated cardiomyopathy remainspoorly understood.
Approximately one third of cases of idiopathic dilated cardiomyopathyare inherited.4,5,6 Although this disorder can be transmittedas a recessive or X-linked trait, autosomal dominant inheritanceoccurs most frequently and exhibits both clinical variabilityand genetic heterogeneity. Adult-onset dilated cardiomyopathy,without accompanying conduction disease or skeletal-muscle abnormalities,has been mapped to six loci, on chromosomes 9q13–q22,710q21–q23,8 1q32,9 2q31,10 2q11–q22,11 and 15q14.12Of these, only one disease-linked gene, that for cardiac actin(on chromosome 15), has been identified. Dilated cardiomyopathyis often accompanied by conduction-system disease, and diseaseloci on chromosomes 3p22–p2513 and 1p1–q2114 havebeen identified. Linkage studies further indicate that the chromosome1p1–q21 locus accounts for an important fraction of casesof dilated cardiomyopathy and conduction-system disease (unpublisheddata).
Emery–Dreifuss muscular dystrophy results in the onsetof contractures of the elbows, Achilles tendons, and postcervicalmuscles in childhood, with slowly progressive wasting and weaknessof the muscles in a humeroperoneal distribution. By adulthood,affected persons have conduction-system disease, most commonlyheart block15,16; left ventricular dilatation and contractiledysfunction are very rare.17,18,19 Emery–Dreifuss musculardystrophy occurs as an X-linked trait, caused by emerin mutations,20,21or as an autosomal dominant disorder resulting from mutationsin the gene encoding lamins A and C.22
Like emerin, lamins A and C are components of the nuclear envelopebut are located in the lamina, a multimeric structure associatedwith the nucleoplasmic surface of the inner nuclear membrane(Figure 1). These highly conserved proteins are transcribedfrom a single gene, LMNA (referred to hereinafter as the laminA/C gene), which is encoded on chromosome 1q21.2–q21.3.29Lamins are structurally homologous with other intermediate filamentsand consist of a central-rod domain flanked by globular aminoand carboxyl domains (Figure 1B).30,31 Hydrophobic repeats withinthe central rod promote formation of an -helical coiled-coildimer, and charged residues along the surface of the coiled-coildimer promote interactions between rod dimers, thereby producingcomplex assembly of the filaments.30,32 Lamins A, C, and B2are expressed in a wide range of tissues, including adult heartand skeletal muscle.33,34 The mechanism by which lamin A/C mutationscause Emery–Dreifuss muscular dystrophy is unknown.
Figure 1. Components of Myocyte Cytoarchitecture (Panel A) and Mutations Causing Dilated Cardiomyopathy and Conduction-System Disease or Autosomal Dominant Emery–Dreifuss Muscular Dystrophy (Panel B).
Mutations in the rod domain of the lamin A/C gene cause isolated dilated cardiomyopathy and conduction-system disease, presumably through perturbed interactions with nuclear or cytoplasmic constituents (Panel A). Other cytoskeletal molecules implicated in the pathophysiology of human dilated cardiomyopathy include actin, dystrophin, and the dystrophin-associated glycoprotein complex.12,23,24,25,26,27,28 Interactions between lamins A and C and cytoskeletal or sarcomere proteins are unknown. Conduction-system disease is a common feature of Emery–Dreifuss muscular dystrophy caused by defects in the head or tail domain of the lamin gene or by emerin mutations. Mutations causing dilated cardiomyopathy and conduction-system disease or autosomal dominant Emery–Dreifuss muscular dystrophy are distributed in distinct domains of the lamin dimer (Panel B). Lamins A and C have identical structures throughout the amino-terminal head (NH3), -helical rod domain, and proximal carboxyl-terminal tail (COOH), but they differ in their distal amino acids (lamin A is shown in gray, and lamin C is shown in black). Mutations in the rod domain (Arg60Gly, Leu85Arg, Asn195Lys, and Glu203Gly) cause dilated cardiomyopathy and conduction-system disease without skeletal myopathy; the mutation at the carboxyl terminal (Arg571Ser) is associated with subclinical skeletal-muscle disease. Mutations that cause Emery–Dreifuss muscular dystrophy (Gln6Stop, Arg453Trp, Arg527Pro, and Leu530Pro) do not affect the -helical rod domain.
On the basis of the chromosomal location of the lamin A/C geneand the cardiovascular phenotype of some adults with Emery–Dreifussmuscular dystrophy, we hypothesized that distinct mutationsin the lamin A/C gene caused dilated cardiomyopathy and conduction-systemdisease in the absence of skeletal myopathy. To test this hypothesis,we sequenced the lamin A/C gene in probands of 11 families andevaluated affected family members for clinical manifestationsof Emery–Dreifuss muscular dystrophy.
Methods
Clinical Evaluation
Written informed consent was obtained from all participantsin accordance with the requirements of the human-research committeeof Brigham and Women's Hospital. All the family members underwentclinical evaluation, including history taking, physical examination,12-lead electrocardiography, and transthoracic echocardiography.Initial clinical evaluations were performed without knowledgeof genotype status. Family members were considered to be affectedif cardiac studies demonstrated sinoatrial dysfunction, atrioventricularconduction-system abnormalities, or left ventricular dysfunction(increased end-diastolic diameter, reduced fractional shortening,or both) in the absence of other known causes.14 The diseasestatus of deceased family members was determined on the basisof a review of their medical records. Deaths were classifiedas disease-related or as due to noncardiac causes, as describedpreviously.10 Family members with lamin A/C mutations underwentfurther evaluations, including a review of their medical history,clinical neuromuscular examination, measurement of serum creatinekinase, and skeletal-muscle biopsy.
Genetic Studies
We obtained 5 to 30 ml of peripheral blood from each familymember who was evaluated. DNA was isolated from whole bloodor lymphocytes transformed by Epstein–Barr virus as describedelsewhere.14 Refined physical mapping of polymorphisms of chromosome1 has recently extended the disease locus at chromosome 1p1–1q114to q21. Genetic linkage to the 1p1–q21 locus was ascertainedin Families A and B with the use of the polymorphic markersD1S305 and D1S506. Two-point lod scores were calculated withthe use of the MLINK program.14
Identification of Mutations in the Lamin A/C Gene
Protein-encoding sequences from exons 1 through 12 were amplifiedfrom genomic DNA with the use of primers derived from intronsequences. The sequences are available on the Internet (at http://genetics.med.harvard.edu/~seidman/lamin.html)or from the National Auxiliary Publications Service (*). Intron–exonboundaries for lamin A/C were obtained from genomic sequencesin the GenBank data base (accession numbers L12399, L12400,and L12401). Genomic DNA fragments amplified with the polymerasechain reaction (PCR) were purified with a PCR purification kit(QIAquick, Qiagen, Santa Clarita, Calif.) to remove the residualprimers and sequenced with a dye-terminator cycle-sequencingsystem (ABI PRISM 377, Perkin–Elmer Applied Biosystems,Foster City, Calif.).
Confirmation of Mutations and Family Genotypes
Five variants in the lamin A/C gene sequences (Figure 2A) wereidentified by sequence analysis and independently confirmedby restriction-enzyme digestion. Exons were amplified by PCRwith the use of primers available on the Internet (at http://genetics.med.harvard.edu/~seidman/lamin.html)or from *, digested with restriction enzyme, and size-fractionatedon a 3 percent Nusieve–1 percent agarose gel. The presenceor absence of sequence variants in DNA samples from family membersand from 75 normal controls was also ascertained by analysesof the results of restriction-enzyme digestion. The Leu85Argmutation (in Family C) abolishes a SacI restriction-enzyme site.Mutations Arg60Gly (Family D), Asn195Lys (Family B), Glu203Gly(Family E), and Arg571Ser (Family A) create Sau96I, MboII, BsmFI,and AlwNI restriction-enzyme sites, respectively.
Figure 2. Isoforms of the Lamin A/C Gene and Sequences of Lamin Proteins.
The lamin A/C gene encodes four isoforms by alternative splicing of the 12 exons that make up the gene (Panel A). Exons 1 through 10 contain sequences shared by all isoforms (stippled bars). Exons 11 and 12 contain sequences (cross-hatched shading) that are found in transcripts of lamin A, and exon 10 contains sequences (hatched shading) that encode lamin C isoforms. The 3' untranslated region (open area) becomes part of the lamin A messenger RNA. The precise sizes of introns 1 and 2 are not known. The nucleotide residues mutated in the lamin A/C gene that were identified in study families and their predicted amino acid substitutions in lamin peptides are indicated in parentheses. A comparison of sequences of lamin proteins among various species (Panel B) indicates that human mutations that cause dilated cardiomyopathy and conduction-system disease occur in highly conserved residues. Dots denote amino acid identity with the human sequence (shown as a single-letter code). There is considerable divergence among species in the sequences of lamin B2 as compared with those of lamins A and C. (The lamin sequences for humans, mice, rats, chickens, and xenopus were obtained from the GenBank data base. In cases in which human lamin B2 sequences were not available, murine sequences are provided.)
Results
Genetic Studies
Autosomal dominant dilated cardiomyopathy and conduction-systemdisease in two families (Families A and B) were assessed forlinkage to the disease locus at chromosome 1p1–q21. Analysesof polymorphic loci D1S305 and D1S506 indicated that there waslinkage of disease to this genomic location in the families(likelihood of coinheritance, 1 in 100 and 1 in 125, respectively).Exon sequences of the lamin A/C gene (Figure 2A) were then analyzedin samples from the probands in these and nine other, unrelatedfamilies with autosomal dominant dilated cardiomyopathy andconduction-system disease. A unique sequence variant was identifiedin the genomes of five unrelated probands, each of which waspredicted to alter one amino acid in the lamin protein. Eachsequence variant was independently confirmed by analysis ofthe results of restriction-enzyme digestion. None of the fivesequence variants were found in more than 150 chromosomes fromnormal persons, demonstrating that these sequence variants arenot common polymorphisms.
Four of the five sequence variants alter 1 of 566 amino acidscommon to isoforms of lamin A and C: Arg60Gly and Leu85Arg areencoded in exon 1; Asn195Lys and Glu203Gly are encoded in exon3. These variants were predicted to alter residues in the -helicalrod domain (coils 1A and 1B) of the peptide. In contrast, themutation Arg571Ser (in exon 10) alters a residue specific tothe carboxyl tail of the lamin C isoform. These five sequencevariants were designated as disease-causing mutations becausethey were found in affected family members but not in unaffectedrelatives more than 30 years of age, because they altered thecharge of the encoded amino acid and therefore would be expectedto perturb the lamin structure considerably, and because eachaltered residue is highly conserved throughout evolution (Figure 2B),indicating that these defects probably have functionalconsequences.
Clinical Features of Lamin A/C Mutations
Clinical evaluations of 85 members of the five families withthe sequence variants identified 39 with cardiovascular disease(Table 1 and Figure 3). Genetic studies in 26 clinically affectedfamily members demonstrated that each was heterozygous for alamin missense mutation. DNA samples were not available from12 deceased family members and 1 affected living member. Twelvefamily members who were less than 30 years of age were heterozygousfor a lamin A/C missense mutation but had neither signs norsymptoms of heart disease.
Figure 3. Pedigrees of Five Families with Lamin A/C Mutations.
Squares indicate male family members, circles female family members, and symbols with a slash mark deceased family members. Rhythm disturbance is shown by symbols that are solid on the left-hand side, and dilated cardiomyopathy by symbols that are solid on the right-hand side. Totally solid symbols indicate the presence of both rhythm disturbance and cardiomyopathy. Open symbols indicate unaffected family members, and shaded symbols those whose status was indeterminate. The presence (+) or absence (–) of a lamin A/C mutation is indicated for persons with DNA samples available for testing.
The natural history of disease was assessed on the basis ofclinical histories of affected members (Table 1) in the fivefamilies. The onset of disease typically occurred early in middleage (mean age, 38 years; range, 19 to 53), and in multiple instancesthe initial presentation was asymptomatic electrocardiographicabnormalities in cardiac rate and rhythm, which were detectedduring routine physical examination. Progressive abnormalitiesin cardiac conduction and atrial fibrillation or flutter becameevident with increasing age (Figure 4A). Thirty-four of the39 affected family members (87 percent) had sinus-node dysfunctionor disturbances in atrioventricular conduction (sinus bradycardiaor first-, second-, or third-degree heart block); 23 affectedmembers (59 percent) had atrial fibrillation or flutter. Twenty-one(54 percent) had pacemakers implanted because of high-gradeatrioventricular block or bradyarrhythmias (sinus bradycardiaor atrial fibrillation with a slow ventricular response).
Figure 4. Electrocardiographic Tracings of Affected Members of Family B.
Serial tracings from one family member (Panel A) show progressive atrioventricular block (from 33 to 37 years of age), paroxysmal atrial fibrillation (at the age of 34 years), and sinus arrest with infrequent junctional escape beats (at the age of 37). Panel B shows a normal electrocardiographic tracing from another family member (V-1), with congestive heart failure and prior paroxysmal episodes of atrial fibrillation, which was obtained one week before his sudden death. There was no delay in atrioventricular conduction.
Twenty-five of the 39 clinically affected family members (64percent) had dilated cardiomyopathy. The age at onset and theseverity of left ventricular dysfunction within each familywere variable; impairment of left ventricular contraction wasmild to moderate in 12 persons, but heart failure developedin 13. Progression of disease was rapid in six members, whorequired cardiac transplantation within three years after diagnosis;two of these six died from accelerated coronary atherosclerosisin the transplanted heart. Eleven family members with dilatedcardiomyopathy died suddenly between the ages of 30 and 59 years:the only prior arrhythmia of one of these was paroxysmal atrialtachyarrhythmia without electrocardiographic evidence of atrioventricularconduction delay (Figure 4B).
Pathological examination of heart tissue explanted during transplantationor obtained at autopsy from affected members of Families B,C, and E identified four-chamber dilatation, myocyte hypertrophy,and fibrosis without inflammation. Detailed histopathologicalstudies35 of the conduction system of a member of Family E revealedmarked fibrosis and fatty metamorphosis of the sinoatrial andatrioventricular nodes, as well as the atrioventricular bundle.
Differences in clinical manifestations of disease were apparentamong the five families. The affected members of Families Band C had a more severe phenotype than the affected membersof Families A, D, and E, and many had atrial fibrillation (91percent of affected members of Family B and 100 percent of affectedmembers of Family C) (Table 1), dilated cardiomyopathy (73 percentand 100 percent, respectively), or sudden death (45 percentand 40 percent). Embolic events occurred in three members ofFamily E (38 percent) but in only one from Family A and onefrom Family B. Affected members of Family A had a relativelymild phenotype, with a low prevalence of atrial fibrillation(38 percent) and dilated cardiomyopathy (38 percent) and nosudden death.
Affected members of each family were evaluated for the presenceof skeletal-muscle involvement indicative of Emery–Dreifussmuscular dystrophy, a disorder also caused by lamin A/C mutations.22Mutations in the -helical rod domain of lamins A and C producedno skeletal-muscle dysfunction, no weakness or wasting, andno joint contractures in any members of Families B, C, D, andE. The serum creatine kinase levels in 15 clinically affectedmembers from these four families were normal. Skeletal-muscle–biopsyspecimens from three members of Family D were normal. A biopsyof the vastus lateralis obtained from one member of Family B,an active jogger, showed mild, nonspecific changes with minimalvariation in fiber size and few internal nuclei (Figure 5A andFigure 5B). Inflammatory cells were not present. Sections exposedto ATPase showed a normal checkerboard pattern of type 1 and2 fibers. Sections exposed to NADH dehydrogenase, periodic acid–Schiff,myophosphorylase, and oil red O were also normal. The markedvariations in the size of muscle fibers and in the degree offibrofatty replacement typically observed in patients with Emery–Dreifussmuscular dystrophy were absent (Figure 5C).
Figure 5. Skeletal-Muscle–Biopsy Specimens from a Member of Family B Who Had Dilated Cardiomyopathy and Conduction-System Disease Caused by the Lamin-Rod Mutation Asn195Lys (Panels A and B), as Compared with Typical Findings of Emery–Dreifuss Muscular Dystrophy (Panel C).
A transverse section of skeletal muscle (Panel A) shows slight variation in fiber size, rare internalized nuclei (arrow), and no evidence of increased endomysial connective tissue (hematoxylin and eosin, x75). Panel B shows a normal checkerboard pattern of type 1 (light) and type 2 (dark) fibers evident on staining with ATPase (pH 9.4, x40). Emery–Dreifuss muscular dystrophy (Panel C) causes widespread loss of muscle fibers, marked variation in fiber size, and extensive infiltrates of fibroadipose connective tissue (hematoxylin and eosin, x40).
The mutation in the lamin C carboxyl tail in Family A causedneither signs nor symptoms of muscular dystrophy. However, serumcreatine kinase levels were elevated in three of six clinicallyaffected family members, as well as in one genetically affected,asymptomatic member (Table 1). Skeletal-muscle biopsies werenot performed for Family A.
Discussion
In the families we studied, lamin A/C mutations caused familialdilated cardiomyopathy associated with conduction-system disease.Defects were identified in 5 of 11 affected families, indicatingthat defects in the lamin A/C gene are a major cause of thisclinical phenotype. Because missense mutations in the tail regionsof lamins A and C cause Emery–Dreifuss muscular dystrophy22and rod mutations cause isolated myocardial disease, we speculatedthat these domains participate in unique interactions in skeletalor cardiac muscle. These data define an important role of nuclear-membranebiology in cardiac conduction and contraction.
Alternate splicing of the 12 exons that make up the lamin A/Cgene produces at least four different types of RNA that encodeclosely related proteins: lamins A, A10, C, and C2.32 LaminsA and C are coexpressed in the nuclear envelope of many tissues,including heart and skeletal muscle.34 The first 566 amino acidsof lamins A and C (encoded in exons 1 through 10) are identical,whereas the carboxyl terminal of these peptides differs in lengthand amino acid sequence (Figure 1B).30
The Arg571Ser mutation, which selectively alters the carboxylterminal of lamin C, caused a relatively milder cardiac phenotypethan mutations in the rod domain of the lamin A/C gene and subclinicaldisease affecting skeletal muscle. Although affected membersof Family A had no skeletal-muscle symptoms, some had elevatedserum creatine kinase levels, including one asymptomatic familymember with the genotype associated with the disease. The Arg571Sermutation affects only lamin C isoforms, whereas previously describeddefects causing Emery–Dreifuss muscular dystrophy perturbboth lamin A and lamin C isoforms. Perhaps mutations in thecarboxyl terminal perturb peptide stability or prevent assemblyof lamin filaments, a process of head-to-tail polymerization.32,36Selective muscle involvement might then reflect a graded responseto deficiencies of lamin C or of lamins A and C. Alternatively,restricted expression of the Arg571Ser mutation in lamin C ordistinct functions of lamin A could account for the disparityin skeletal-muscle involvement.
Four missense mutations in the rod domains of isoforms of laminsA and C that caused isolated cardiac disease would be expectedto function through a dominant negative mechanism. Amino acidsubstitutions that alter charge, hydrophobicity, or both shoulddisrupt -helical–rod structure, but such defects are unlikelyto function as null alleles. This hypothesis is supported byclinical findings: the null allele G1n6Stop22 causes autosomaldominant Emery–Dreifuss muscular dystrophy, whereas defectsin the rod domain of the lamin A/C gene have no consequencein terms of skeletal-muscle function. Family members with missensemutations in the rod domain of the lamin A/C gene had normalmuscle strength, normal muscle morphology, no joint contractures,and normal serum creatine kinase levels, but they did have cardiacdisease characterized by sinus-node dysfunction, atrioventricular-nodedysfunction, or both and dilated cardiomyopathy with onset inadulthood. Although disturbances of cardiac rhythm develop inthe majority of patients with Emery–Dreifuss musculardystrophy,15,16,17,18,19 important differences were found inthose with the cardiac phenotypes caused by mutations in therod domain of the lamin A/C gene. These defects are highly penetrant,and, by the fourth decade of life, they uniformly produced cardiacdisease with hemodynamically important bradyarrhythmias andtachyarrhythmias (97 percent) and a high incidence of suddendeath (28 percent), thromboembolic events (13 percent), andcongestive heart failure (33 percent). Despite the related molecularcauses of Emery–Dreifuss muscular dystrophy and dilatedcardiomyopathy with conduction-system disease, we suggest thatthere is clinical value in recognizing each as a distinct diseaseentity.
How do lamin defects cause heart disease? Nuclear lamins contributeto the structural integrity of the nuclear envelope and providemechanical support for the nucleus.36 These molecules interactwith nuclear components. In dividing cells, they have a dynamicrole in the organization of interphase chromatin and the reassemblyof nuclear membrane during mitosis.37,38,39 In nondividing cells,lamins may participate in signal transduction by mediating molecularmovement between the cytoplasm and the nucleus.40 Hence, onepossible effect of lamin mutations may be the disruption ofnuclear function, resulting in cell death. Myocyte loss couldaccount for the postmortem finding of extensive fibrofatty infiltrationof the myocardium and conduction system in one member of FamilyE,35 and for that found in the skeletal muscles of patientswith Emery–Dreifuss muscular dystrophy (Figure 5C). Alternatively,missense mutations in the rod domain of the lamin A/C gene mayalter interactions with cytoplasmic proteins (in particular,intermediate filament components of the sarcomere, the actin-basedcytoskeleton, and the sarcolemma) (Figure 1A), some of whichhave been implicated in dilated cardiomyopathy,12,23,24,25,26,27,28although direct interactions between lamin A or lamin C andthese components have not been demonstrated to date. Defininghow lamin mutations alter cardiac-cell biology should ultimatelyincrease our understanding of the pathophysiology of dilatedcardiomyopathy. More immediately, these data implicate genesencoding other lamin proteins and associated components of thenuclear membrane as a cause of the cardiac or skeletal myopathythat occurs with conduction-system disease.
Supported by the Stanley J. Sarnoff Endowment and the MarshfieldMedical Research Foundation and by grants from the NationalInstitutes of Health and the Howard Hughes Medical Institute.
We are indebted to the participating families and their physicians,without whose invaluable assistance these studies would nothave been possible; to Barend P. Lotz, M.D., Andrew J. Waclawik,M.D., and M. Shahriar Salamat, M.D., Ph.D., for preparationand analysis of muscle-biopsy specimens; to Spencer Kubo, M.D.,D. Woodrow Benson, M.D., and Kristin Patton, M.D., for participatingin the clinical evaluations; to Cathy Duffy for assistance inDNA analysis; and to Susanne Bartlett for assistance with thefigures.
* See NAPS document no. 05534 for 4 pages of supplementary material.To order, contact NAPS c/o Microfiche Publications, 248 HempsteadTpk., West Hempstead, NY 11552.
Source Information
From the Cardiovascular Division and Howard Hughes Medical Institute (D.F., C.E.S.) and the Division of Neuropathology (U.D.G.), Brigham and Women's Hospital, Boston; the Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston (C.M., T.S., S.S., J.G.S., C.E.S.); the Cardiovascular Division, University of Wisconsin School of Medicine, Madison (M.R.W.); the Cardiovascular Division, Hospital G. Brotzu, Cagliari, Italy (M.P.); the Department of Cardiology, University of Wales College of Medicine, Wales Heart Research Institute, Cardiff, United Kingdom (M.F.); the Department of Cardiology, Royal Brisbane Hospital, Brisbane, Australia (J.A.); and the Cardiovascular Division, Marshfield Clinic, Marshfield, Wis. (H.J.V.). Drs. Fatkin, MacRae, and Sasaki contributed equally to the article.Other authors were Francesco Muntoni, M.D., Hammersmith Hospital, London; Gerry Müehle, B.Sc., Royal Brisbane Hospital, Brisbane, Australia; and Wendy Johnson, M.D., and Barbara McDonough, R.N., Brigham and Women's Hospital, Boston.
Address reprint requests to Dr. C.E. Seidman at the Department of Genetics, Harvard Medical School, Alpert Rm. 533, 200 Longwood Ave., Boston, MA 02115, or at cseidman{at}rascal.med.harvard.edu.
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(2003). A synonymous codon change in the LMNA gene alters mRNA splicing and causes limb girdle muscular dystrophy type 1B. J. Med. Genet.
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Sebillon, P, Bouchier, C, Bidot, L D, Bonne, G, Ahamed, K, Charron, P, Drouin-Garraud, V, Millaire, A, Desrumeaux, G, Benaiche, A, Charniot, J-C, Schwartz, K, Villard, E, Komajda, M
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Holt, I., Ostlund, C., Stewart, C. L., Man, N. t., Worman, H. J., Morris, G. E.
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Cooper, S. T., Lo, H. P., North, K. N.
(2003). Single section Western blot: Improving the molecular diagnosis of the muscular dystrophies. Neurology
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Michels, V V, Driscoll, D J, Miller, F A, Olson, T M, Atkinson, E J, Olswold, C L, Schaid, D J
(2003). Progression of familial and non-familial dilated cardiomyopathy: long term follow up. Heart
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Darbar, D., Herron, K. J., Ballew, J. D., Jahangir, A., Gersh, B. J., Shen, W.-K., Hammill, S. C., Packer, D. L., Olson, T. M.
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Taylor, M. R. G., Fain, P. R., Sinagra, G., Robinson, M. L., Robertson, A. D., Carniel, E., Di Lenarda, A., Bohlmeyer, T. J., Ferguson, D. A., Brodsky, G. L., Boucek, M. M., Lascor, J., Moss, A. C., Li, W.-L. P., Stetler, G. L., Muntoni, F., Bristow, M. R., Mestroni, L., Familial Dilated Cardiomyopathy Registry Research,
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Doevendans, P. A.
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Caux, F., Dubosclard, E., Lascols, O., Buendia, B., Chazouilleres, O., Cohen, A., Courvalin, J.-C., Laroche, L., Capeau, J., Vigouroux, C., Christin-Maitre, S.
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Muntoni, F.
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Aronson, I. K., Fiedler, V. C.
(2003). Of Mice and Men: The Road to Understanding the Complex Nature of Adipose Tissue and Lipoatrophy. Arch Dermatol
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Kumaran, R. I., Muralikrishna, B., Parnaik, V. K.
(2002). Lamin A/C speckles mediate spatial organization of splicing factor compartments and RNA polymerase II transcription. J. Cell Biol.
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Bowles, N.E.
(2002). The molecular biology of dilated cardiomyopathy. Eur Heart J Suppl
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Fatkin, D., Graham, R. M.
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van der Kooi, A. J., Bonne, G., Eymard, B., Duboc, D., Talim, B., Van der Valk, M., Reiss, P., Richard, P., Demay, L., Merlini, L., Schwartz, K., Busch, H. F.M., de Visser, M.
(2002). Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy. Neurology
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Dhe-Paganon, S., Werner, E. D., Chi, Y.-I., Shoelson, S. E.
(2002). Structure of the Globular Tail of Nuclear Lamin. J. Biol. Chem.
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Crispell, K. A., Hanson, E. L., Coates, K., Toy, W., Hershberger, R. E.
(2002). Periodic rescreening is indicated for family members at risk of developing familial dilated cardiomyopathy. J Am Coll Cardiol
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Lloyd, D. J., Trembath, R. C., Shackleton, S.
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Arbustini, E., Pilotto, A., Repetto, A., Grasso, M., Negri, A., Diegoli, M., Campana, C., Scelsi, L., Baldini, E., Gavazzi, A., Tavazzi, L.
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Raharjo, W. H., Enarson, P., Sullivan, T., Stewart, C. L., Burke, B.
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[Abstract][Full Text]
-helical rod domain of the lamin A/C gene, and one in the lamin C tail domain. Each mutation caused heritable, progressive conduction-system disease (sinus bradycardia, atrioventricular conduction block, or atrial arrhythmias) and dilated cardiomyopathy. Heart failure and sudden death occurred frequently within these families. No family members with mutations had either joint contractures or skeletal myopathy. Serum creatine kinase levels were normal in family members with mutations of the lamin rod but mildly elevated in some family members with a defect in the tail domain of lamin C. 
10, C, and C2.32 Lamins A and C are coexpressed in the nuclear envelope of many tissues, including heart and skeletal muscle.34 The first 566 amino acids of lamins A and C (encoded in exons 1 through 10) are identical, whereas the carboxyl terminal of these peptides differs in length and amino acid sequence (Figure 1B).30 
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