Gene discovery report:

McNair WP, Ku L, Taylor MR, Fain PR, Dao D, Wolfel E, Mestroni L. SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia. Circulation. 2004 Oct 12;110(15):2163-7

Other SCN5A reports:

Olson TM, Michels VV, Ballew JD, Reyna SP, Karst ML, Herron KJ, Horton SC, Rodeheffer RJ, Anderson JL. Sodium channel mutations and susceptibility to heart failure and atrial fibrillation. JAMA. 2005 Jan 26;293(4):447-54.

 

 

Gene discovery report:

Duboscq-Bidot, L., et al. Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy. Cardiovasc Res. 2008. 77(1): p. 118-25.

 

A Brief Review of LMNA, the Gene That Encodes the Lamin A/C Protein.

Because its overall significance for FDC, a brief overview of lamin A/C molecular genetics is  provided here.

The molecular genetics of the LMNA gene has been an exciting series of discoveries of diverse disease phenotypes ranging from skeletal and cardiac myopathy to endocrine and neurological disease, and most recently to progeria, the rare syndrome of premature aging (1-4).

The LMNA gene resides on chromosome 1 (1q21.2-.3) and encodes 4 isoforms by alternative splicing of its 12 exons; exons 1-10 are common to both. Lamins A and C are components of the nuclear membrane located in the lamina, a structure associated with the nucleoplasmic surface of the inner nuclear membrane (5). Lamins also interact with DNA and may modulate gene expression (6).

Lamin A/C was first implicated in human disease as the cause of autosomal dominant (AD) Emery-Dreifuss muscular dystrophy (of which heart block may be a feature) (7, 8), and then AD limb-girdle muscular dystrophy (LGMD1B) (9). Emery-Dreiffuss muscular dystrophy preferentially affects the muscles of the upper arms and shoulders, and upper legs.

Numerous publications since the 1999 initial report (10) have documented lamin A/C mutations with DCM. Selected reports with larger kindreds to illustrate the age-dependent onset and variable phenotype, including usually conduction system disease followed by later onset of DCM and heart failure have been selected (11-16). Links with brief reviews of these reports follow.

Mutations in LMNA also cause  familial lipodystrophy, a rare condition where adipocytes involute in adolescence, frequently followed by glucose intolerance and/or diabetes (17-19). Each of these conditions can be caused by point mutations. Aside from the few mutations that cause familial partial lipodystrophy that are clustered in the tail portion of lamin A/C, mutations for muscular dystrophy or cardiomyopathy have been reported in all exons of lamin A/C. That is, mutations appear to be the so-called ‘private mutations’ where most families reported thus far have their own mutation. Hence, for molecular diagnosis, screening or sequencing of the entire lamin A/C gene is required.

The mechanism of disease for DCM  and muscular dystrophy remains unknown. It has been proposed that mutations in LMNA may adversely affect the structural integrity of the lamin A/C protein of the nuclear membrane in cardiac myocytes with constant motion (5); and alternative hypothesis suggests that gene expression may be altered (1).

Mutations in the lamin A/C gene may be the most common genetic cause of FDC, and may account from between 5-10% of mutations (15).

Links to Lamin A/C Reports in Dilated Cardiomyopathy:

The Fatkin/Seidman 1999 NEJM report.

The Becane 2000 Report.

The Jakobs 2001 Report.

The Hershberger 2002 Report.

The Taylor 2003 Report.

The Arbustini 2003 Report.

The Sebillion 2003 Report.

The Parks 2008 Report.

References for this page

1.         Wilson, KL, Zastrow MS, Lee KK, Lamins and disease: insights into nuclear infrastructure. Cell 2001;104:647-50. PMID: 11257219.

2.         Novelli, G,D’Apice MR, The strange case of the “lumper” lamin A/C gene and human premature ageing. Trends Mol Med 2003;9:370-5. PMID: 13129702.

3.         Eriksson, M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS, Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 2003;423:293-8. PMID: 12714972.

4.         Worman, HJ,Courvalin JC, How do mutations in lamins A and C cause disease? J Clin Invest 2004;113:349-51. PMID: 14755330.

5.         Hutchison, CJ, Alvarez-Reyes M, Vaughan OA, Lamins in disease: why do ubiquitously expressed nuclear envelope proteins give rise to tissue-specific disease phenotypes? J Cell Sci 2001;114:9-19. PMID: 11112685.

6.         Wilson, KL, The nuclear envelope, muscular dystrophy and gene expression. Trends Cell Biol 2000;10:125-9. PMID: 0010740265.

7.         Bonne, G, Di Barletta MR, Varnous S, Becane HM, Hammouda EH, Merlini L, Muntoni F, Greenberg CR, Gary F, Urtizberea JA, Duboc D, Fardeau M, Toniolo D, Schwartz K, Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nature Genetics 1999;21:285-288. PMID: 10080180.

8.         Raffaele Di Barletta, M, Ricci E, Galluzzi G, Tonali P, Mora M, Morandi L, Romorini A, Voit T, Orstavik KH, Merlini L, Trevisan C, Biancalana V, Housmanowa-Petrusewicz I, Bione S, Ricotti R, Schwartz K, Bonne G, Toniolo D, Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy. Am J Hum Genet 2000;66:1407-12. PMID: 10739764.

9.         Muchir, A, Bonne G, van der Kooi AJ, van Meegen M, Baas F, Bolhuis PA, de Visser M, Schwartz K, Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet 2000;9:1453-9. PMID: 0010814726.

10.       Fatkin, D, MacRae C, Sasaki T, Wolff M, Porcu M, Frenneaux M, Atherton J, Vidaillet H, Spudich S, Girolami U, Seidman J, Seidman C, Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999;341:1715-24. PMID: 10580070.

11.       Becane, HM, Bonne G, Varnous S, Muchir A, Ortega V, Hammouda EH, Urtizberea JA, Lavergne T, Fardeau M, Eymard B, Weber S, Schwartz K, Duboc D, High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing Clin Electrophysiol 2000;23:1661-6. PMID: 11138304.

12.       Jakobs, PM, Hanson E, Crispell KA, Toy W, Keegan H, Schilling K, Icenogle T, Litt M, Hershberger RE, Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease. J Card Fail 2001;7:249-256. PMID: 1151226.

13.       Hershberger, RE, Hanson E, Jakobs PM, Keegan H, Coates K, Bousman S, Litt M, A novel lamin A/C mutation in a family with dilated cardiomyopathy, prominent conduction system disease, and need for permanent pacemaker implantation. Am Heart J 2002;144:1081-6. PMID: 12486434.

14.       Arbustini, E, Pilotto A, Repetto A, Grasso M, Negri A, Diegoli M, Campana C, Scelsi L, Baldini E, Gavazzi A, Tavazzi L, Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease. J Am Coll Cardiol 2002;39:981-90. PMID: 11897440.

15.       Taylor, MR, Fain PR, Sinagra G, Robinson ML, Robertson AD, Carniel E, Di Lenarda A, Bohlmeyer TJ, Ferguson DA, Brodsky GL, Boucek MM, Lascor J, Moss AC, Li WL, Stetler GL, Muntoni F, Bristow MR, Mestroni L, Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 2003;41:771-80. PMID: 12628721.

16.       Sebillon, P, Bouchier C, Bidot LD, Bonne G, Ahamed K, Charron P, Drouin-Garraud V, Millaire A, Desrumeaux G, Benaiche A, Charniot JC, Schwartz K, Villard E, Komajda M, Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations. J Med Genet 2003;40:560-7. PMID: 12920062.

17.       Speckman, RA, Garg A, Du F, Bennett L, Veile R, Arioglu E, Taylor SI, Lovett M, Bowcock AM, Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C. Am J Hum Genet 2000;66:1192-8. PMID: 0010739751.

18.       Shackleton, S, Lloyd DJ, Jackson SN, Evans R, Niermeijer MF, Singh BM, Schmidt H, Brabant G, Kumar S, Durrington PN, Gregory S, O’Rahilly S, Trembath RC, LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet 2000;24:153-6. PMID: 0010655060.

19.       Cao, H,Hegele RA, Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan- type familial partial lipodystrophy. Hum Mol Genet 2000;9:109-12. PMID: 0010587585.

 

Lamin DCM Reports.

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Title. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.

Authors. Fatkin D, MacRae C, Sasaki T, Wolff MR, Porcu M, Frenneaux M, Atherton J, Vidaillet HJ Jr, Spudich S, De Girolami U, Seidman JG, Seidman C, Muntoni F, Muehle G, Johnson W, McDonough B.

Journal. N Engl J Med 1999;341:1715-24.

Cardiovascular Division and Howard Hughes Medical Institute, Brigham and Women’s Hospital, Boston, MA, USA.

PMID: 10580070

Citation type: phenotype/genotype (clinical and genetic data).

Study design:

Study Summary: In this carefully prepared landmark report, 5 lamin A/C missense mutations were reported in 5 of 11 families with DCM and conduction system disease from the laboratory of Kricket and Jon Seidman. The onset of clinically apparent cardiovascular disease in the 39 subjects from these 5 families was in early middle age (average of 38 years, range 19-53), usually with asymptomatic electrocardiographic abnormalities of rate and rhythm. Most subjects then progressed to sinus node or AV node dysfunction, or first, second or third degree heart block; over one-half had atrial fibrillation or flutter, and over one-half required pacemakers. Despite prominent arrhythmias, two-thirds also developed dilated cardiomyopathy that ranged from mild LV dysfunction (12 subjects) to heart failure (13 subjects); 6 subjects required cardiac transplantation, and eleven subjects died suddenly. The severity and type of cardiovascular disease varied within and between the five families. Penetrance appeared to be 100% in the 33 carriers >30 years from these five families No evidence of muscular dystrophy was observed.

Comment: This was the initial report of lamin A/C cardiomyopathy that provides the spectrum of disease evident among and between families. Although the initial report, it remains a key publication to understand the clinical and genetic variability of lamin A/C cardiomyopathy.

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Title. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation.

Authors. Becane HM, Bonne G, Varnous S, Muchir A, Ortega V, Hammouda EH, Urtizberea JA, Lavergne T, Fardeau M, Eymard B, Weber S, Schwartz K, Duboc D.

Journal. Pacing Clin Electrophysiol 2000;23:1661-6.

Institut de Myologie, G.H. Pitie-Salpetriere, Paris, France.

PMID: 11138304

Citation type: phenotype/genotype (clinical and genetic data).

Study design: Family report of lamin A/C mutation.

Study measurements:

Study Summary: This was one of the very large linkage French linkage families with prominent skeletal myopathy that contributed to the discovery of lamin A/C as the cause of autosomal dominant Emery-Driefuss muscular dystrophy (MD). This extended kindred had skeletal myopathy/MD, but also had prominent cardiovascular findings especially in deceased family members that resulted from a nonsense mutation in the first exon of LMNA. This kindred probably represents the best example of combined MD and cardiomyopathy, where both presented prominent disease. In contrast, most of the kindreds with lamin A/C cardiomyopathy have shown no skeletal muscle disease.

Of 72 members of this family, 54 underwent clinical screening, including 13 deceased subjects who had medical records reviewed. Eight had died of sudden cardiac death, and 5 died of heart failure. Of the 12 family members who presented with cardiovascular disease, all presented as adults, the youngest at 29 years, 7 in their 30s, 2 at 42 and 46, one at 53, and one at 64 years. Presenting signs/symptoms were those of conduction system disease, including disorders of AV conduction (6 pacemakers in subjects ranging from 35-57 years), atrial flutter or fibrillation (1 and 3 patients, respectively). Some had ventricular arrhythmias also, several had heart failure, and two received heart transplants (ages 36 and 55 years).

Of the 5 patients who presented with skeletal muscle involvement, 2 presented in childhood and 3 in adolescence, usually with elevated creatine kinases; all eventually developed cardiovascular manifestations, but not until adulthood (ages of 23, 31, 36, 44 and 56 years), with the usual progression from conduction system disease to DCM and heart failure; one received a heart transplant at 37 years.

Comment: This large family provides considerable valuable clinical detail that demonstrates the range of phenotypic presentation of both cardiovascular and skeletal muscle involvement with lamin A/C cardiomyopathy.

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Title. Novel lamin A/C mutations in two familes with dilated cardiomyopathy and conduction system disease.

Authors. Jakobs PM, Hanson E, Crispell KA, Toy W, Keegan H, Schilling K, Icenogle T, Litt M, Hershberger RE.

Journal. J Cardiac Failure 2001;7:249-256.

Department of Medicine, Oregon Health Sciences University, Portland, OR

PMID: 11561226

Citation type: phenotype/genotype (clinical and genetic data).

Study design: mutation screening of a subset of large families

Study measurements:

Study Summary: This report from our group provides details of two large families that were suitable for linkage analysis, that upon screening were found to have lamin A/C mutations. Both families presented with progressive conduction system disease, Family A in the 4th and 5th decades with a missense mutation, followed by DCM and heart failure. Conduction system disease included first, second and third degree AV blocks, atrial flutter and fibrillation, some left bundle branch block, and some need for permanent pacemakers. Several mutation positive individuals in their 20s and 30s had no manifestations of disease. Family B had a nonsense mutation with earlier onset of conduction system disease onset in the 3rd and 4th decade, followed by DCM and heart failure. Conduction system disease in this family also had first degree AV block, some paroxysmal atrial tachycardia, some atrial fibrillation, need for permanent pacemakers, and perhaps more ventricular arrhythmias and sudden cardiac death. Usually mild systolic dysfunction without heart failure was evident with or soon after the onset of conduction system disease. Seven subjects in their 20s had clinically evident disease, whereas none of Family A had clinically evident disease in their 20s. Death in both families was caused by heart failure or sudden cardiac death. Subjects from both families had undergone cardiac transplantation. No skeletal muscle disease was observed.

Comment: These large families add to the lamin A/C literature to present the variable age on onset and disease presentation within and between families.

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Title. A novel lamin A/C mutation in a family with dilated cardiomyopathy, prominent conduction system disease and need for permanent pacemaker implantation.

Authors. Hershberger RE, Hanson EL, Jakobs PM, Keegan, Coates K, Bousman S, Litt M.

Journal. Am Heart J  2002;144:1081-1086.

Department of Medicine, Oregon Health and Science University, Portland, OR

PMID: 12486434

Citation type: phenotype/genotype (clinical and genetic data).

Study design: report of a family with a lamin A/C gene mutation.

Study measurements:

Study Summary: This report summarizes a large family with a lamin A/C gene missense mutation that manifest clinical disease largely as conduction system disease, particularly brady- and tachy-arrhythmias necessitating permanent pacemaker implantation in 7 of the 8 clinically affected subjects (88%). Disease onset ranged from 25 to 43 years of age. Two had DCM and heart failure. No skeletal muscle disease was observed.

Comment: This family illustrates the spectrum of lamin A/C disease with greater prominence of conduction system disease. Table 2 in this publication summarizes the numbers of subjects by family (and percent of each family) who had conduction system disease (AV block, Atrial flutter/fibrillation, pacemakers), DCM, heart failure and skeletal muscle disease of the first 10 large families published.

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Title.  Natural history of dilated cardiomyopathy due to lamin A/C gene mutations.

Authors. Taylor MR, Fain PR, Sinagra G, Robinson ML, Robertson AD, Carniel E, Di Lenarda A, Bohlmeyer TJ, Ferguson DA, Brodsky GL, Boucek MM, Lascor J, Moss AC, Li WL, Stetler GL, Muntoni F, Bristow MR, Mestroni L

Journal. J Am Coll Cardiol 2003;41:771-80.

University of Colorado Cardiovascular Institute, Denver, Colorado

PMID: 12628721

Citation type: phenotype/genotype (clinical and genetic data).

Study design: mutation screening for lamin A/C gene mutations in a cohort of FDC and IDC patients.

Study measurements:

Study Summary: DNA from index patients from 40 different families with DCM and 9 sporadic cases were screened for lamin A/C mutations using denaturing high performance liquid chromatography. 3 of the 40 families and 1 sporadic DCM had lamin A/C mutations (4 of 49 = 8%). One frameshift mutation in exon 6 had been previously reported (Brodsky G, Muntoni F, Miocic S, Sinagra G, Sewry C, Mestroni L. Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement. Circ 2000;101:473-476) in a family with skeletal muscle involvment. Conduction system disease was prominent, accompanied or followed by DCM. Comparison of subjects with lamin A/C mutations with those of the cohort with no lamin A/C mutations suggested poorer survival.

Comment: this publication provides a Table showing greater than 40 mutations (through mid-2002) reported to cause lamin A/C cardiomyopathy.

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

Authors.  Arbustini E, Pilotto A, Repetto A, Grasso M, Negri A, Diegoli M, Campana C, Scelsi L, Baldini E, Gavazzi A, Tavazzi L.

Journal.  J Am Coll Cardiol 2002;39:981-90.

Molecular Diagnostic Division, IRCCS Policlinico San Matteo, Pavia, Italy

PMID: 11897440

Citation type: phenotype/genotype (clinical and genetic data).

Study design: mutation screening for lamin A/C gene mutations in a cohort of IDC patients, some with familial conduction system disease.

Study measurements:

Study Summary: Mutations in the lamin A/C gene were screened in 73 probands from Pavia, Italy, and 5 new mutations were found, all within 15 families with atrioventricular block. Of the 33 family members from the 5 families with clinical data available, 16 had DCM and atrioventricular block, 3 had only atrioventricular block. The onset and progression of disease varied, with Family B with rapidly progressive disease to DCM, heart failure and need for transplantation, whereas Families A, C and E had a long interval between onset of clinically evident disease, usually conduction system disease, and DCM. Many presented in their 20s and 30s. Some ventricular arrhythmias were observed.

Comment: This informative report adds to the overall clinical variability of disease presentation and progression.

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Title. Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations.

Authors. Sebillon P, Bouchier C, Bidot LD, Bonne G, Ahamed K, Charron P, Drouin-Garraud V, Millaire A, Desrumeaux G, Benaiche A, Charniot JC, Schwartz K, Villard E, Komajda M.

Journal. J Med Genet 2003;40:560-7.

Laboratoire Genetique et Insuffisance Cardiaque, Association Claude Bernard/Universite Paris VI, Groupe Hospitalier Pitie-Salpetriere, Paris, France.

PMID: 12920062

Citation type: phenotype/genotype (clinical and genetic data).

Study design: mutation screening for lamin A/C gene mutations in a cohort of FDC and IDC patients.

Study measurements:

Study Summary: The DNA from 47 index patients from families with FDC and 19 patients with sporadic DCM were screened for lamin A/C mutations using an SSCP approach. Two missense mutations and one insertion were identified from 3 families (3 of 47 = 6.4%); no mutations were identified in the sporadic cases. Clinical manifestations varied widely between conduction system disease (AV block, atrial fibrillation and need for pacemakers) and heart failure, and age of onset (from 2nd to 6th decade); some skeletal muscle disease was seen in one pedigree.

Comment: The large families presented add to the lamin A/C literature and again illustrate the variable age of onset and clinical manifestations of lamin A/C cardiomyopathy.

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Title.Lamin A/C mutation analysis in a cohort of 324 unrelated patients with idiopathic or familial dilated cardiomyopathy.

Authors.Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Peterson A, Li D, Jakobs P, Litt M, Porter C, Rahko P, Hershberger RE.

Journal. Am Heart J. 2008;156:161-9.

Department of Medicine, Oregon Health and Science University, Portland, OR

PMID:18585512

Citation type: phenotype/genotype (clinical and genetic data).

Study design: mutation screening for lamin A/C gene mutations in a cohort of FDC and IDC patients.

Study measurements:

Study Summary: The frequency of mutations in LMNA was analyzed in 324 unrelated patients with idiopathic (IDC) or familial dilated cardiomyopathy (FDC). A total of 18 protein-altering LMNA variants in 19 probands or 5.9% of all cases (7.5% of FDC; 3.6% of IDC) were identified. Conduction system disease and DCM were common in carriers of LMNA variants. In 6 of the 19 kindreds with a protein-altering LMNA variant (32%), at least one affected family member was negative for the LMNA variant. This unexpected finding suggests that some protein-altering LMNA variants are not causative or that some proportion of FDC may be because of multiple causative factors.

Comment: This is, to our knowledge, the largest cohort to be sequenced for LMNA gene mutations. LMNA mutation frequency is similar in familial and non familial cases. This study also shows that a second DCM gene mutation may be present in some LMNA families.