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FB2026_01
,
released March 12, 2026
This report describes dilated cardiomyopathy 1A (CMD1A), which is a subtype of dilated cardiomyopathy; CMD1A exhibits an autosomal dominant pattern of inheritance. The human gene implicated in this disease is LMNA, which encodes the intermediate filament protein lamin A/C. There are multiple lamins in both humans and flies: the human genes LMNA, LMNB2 and LMNB1 are orthologous to fly genes Dmel\Lam and Dmel\LamC. Classical amorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both fly genes. LMNA is associated with many other diseases (see MIM:150330), including several forms of muscular dystrophy (FBhh0000196) and Hutchinson-Gilford progeria (MIM:176670, FBhh0000176). Association of LMNA variants with dilated cardiomyopathy is supported by a large-scale WES analysis, especially in the cases of truncated variants of the gene (Walsh, et al., 2016; pubmed:27532257).
This subtype of dilated cardiomyopathy is one of several cases in which the implicated gene is also associated with muscular dystrophy (MD). In addition, dilated cardiomyopathy is frequently one of the symptoms of MD. Muscular dystrophy is a genetically heterogeneous disease with many implicated genes; the same gene may be associated with different levels of severity of disease or different subsets of muscles affected. See the human disease model report 'muscular dystrophy, lamin-related' (FBhh0000196).
Multiple UAS and heat-shock constructs of the human Hsap\LMNA gene have been introduced into flies, including wild-type LMNA, mutant protein isoforms, and deletion constructs; mutant forms correspond to variants implicated in Hutchinson-Gilford progeria (FBhh0000176).
For many LMNA mutations associated with disease in humans, analogous mutations in the fly LamC gene have been characterized. Among the variants associated specifically with CMD1A, several have been assessed in Drosophila; see the Disease-Implicated Variants' table below. The G449V variant (G489V in the fly LamC gene), associated with muscular dystrophy (see FBhh0000196), has been used in an assay in which expression of the variant is restricted to the fly heart for assessment of cardiomyopathy.
Amorphic alleles of both Dmel\LamC and Dmel\Lam are lethal, usually in the larval or pupal stage. For hypomorphic alleles, surviving adults show reduced viability, locomotion defects, and various visible phenotypes. Heart-specific expression of LamC mutations analogous to variants implicated in cardiomyopathy result in progressive cardiac dysfunction, loss of adipose tissue homeostasis, and a shortened adult lifespan. Genetic and physical interactions have been described for both genes; see the LamC and Lam gene reports.
[updated Oct. 2022 by FlyBase; FBrf0222196]
Nonsyndromic isolated dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and systolic dysfunction, a reduction in the myocardial force of contraction. DCM usually presents with any one of the following: (1) Heart failure with symptoms of congestion (edema, orthopnea, paroxysmal nocturnal dyspnea) and/or reduced cardiac output (fatigue, dyspnea on exertion); (2) arrhythmias and/or conduction system disease; (3) thromboembolic disease (from left ventricular mural thrombus) including stroke. [from Dilated Cardiomyopathy Overview, pubmed:20301486 2016.01.26]
Dilated cardiomyopathy (CMD) is characterized by cardiac dilatation and reduced systolic function. CMD is the most frequent form of cardiomyopathy and accounts for more than half of all cardiac transplantations performed in patients between 1 and 10 years of age. A heritable pattern is present in 20 to 30% of cases. Most familial CMD pedigrees show an autosomal dominant pattern of inheritance, usually presenting in the second or third decade of life (summary by Levitas et al., 2010, pubmed:20551992). [from MIM:115200, 2016.01.27]
[CARDIOMYOPATHY, DILATED, 1A; CMD1A](https://omim.org/entry/115200)
[LAMIN A/C; LMNA](https://omim.org/entry/150330)
LMNA-related dilated cardiomyopathy (DCM) is caused by mutations in LMNA and is characterized by left ventricular enlargement and reduced systolic function preceded or accompanied by significant conduction system disease and/or arrhythmias. LMNA-related DCM usually presents in early to mid-adulthood with symptomatic conduction system disease or arrhythmias, or with symptomatic DCM including heart failure or embolus from a left ventricular mural thrombus. Sudden cardiac death can occur, and in some instances is the presenting manifestation; sudden cardiac death may occur with little systolic dysfunction. [from GeneReviews, LMNA-Related Dilated Cardiomyopathy, pubmed:20301717 2016.02.04]
In 5 of 11 families with autosomal dominant dilated cardiomyopathy and conduction system defects, Fatkin et al. (1999, pubmed:10580070) identified 5 heterozygous missense mutations in the LMNA gene. 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. Furthermore, serum creatine kinase levels were normal in family members with mutations in the lamin rod domain, but mildly elevated in some family members with a defect in the tail domain of lamin C. The findings indicated that the lamin A/C intermediate filament protein plays an important role in cardiac conduction and contractility.[From MIM:115200 and MIM:150330, 2016.02.01]
Variants predicted to produce a truncated protein are strongly correlated with development of dilated cardiomyopathy (Walsh, et al., 2016; pubmed:27532257).
Dilated cardiomyopathy-1A (CMD1A) is caused by heterozygous mutation in the lamin A/C gene (LMNA). Allelic disorders include the autosomal dominant form of Emery-Dreifuss muscular dystrophy (MIM:181350) and Hutchinson-Gilford progeria syndrome (MIM:176670), among others. [From MIM:115200, 2016.02.01]
The LMNA gene encodes lamin A and lamin C. Lamins are structural protein components of the nuclear lamina, a protein network underlying the inner nuclear membrane that determines nuclear shape and size. The lamins constitute a class of intermediate filaments. Three types of lamins, A, B (see LMNB1; MIM:150340), and C, have been described in mammalian cells (Fisher et al., 1986, pubmed:3462705). [From MIM:150330, 2016.02.01]
Many to many: 3 human to 2 Drosophila.