Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases
Mutations in the <i>LMNA</i> gene cause a collection of diseases known as laminopathies, including muscular dystrophies, lipodystrophies, and early-onset aging syndromes. The <i>LMNA</i> gene encodes A-type lamins, lamins A/C, intermediate filaments that form a meshwork under...
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| Format: | Article |
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MDPI AG
2023-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/8/1142 |
| _version_ | 1797606027777015808 |
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| author | Sydney G. Walker Christopher J. Langland Jill Viles Laura A. Hecker Lori L. Wallrath |
| author_facet | Sydney G. Walker Christopher J. Langland Jill Viles Laura A. Hecker Lori L. Wallrath |
| author_sort | Sydney G. Walker |
| collection | DOAJ |
| description | Mutations in the <i>LMNA</i> gene cause a collection of diseases known as laminopathies, including muscular dystrophies, lipodystrophies, and early-onset aging syndromes. The <i>LMNA</i> gene encodes A-type lamins, lamins A/C, intermediate filaments that form a meshwork underlying the inner nuclear membrane. Lamins have a conserved domain structure consisting of a head, coiled-coil rod, and C-terminal tail domain possessing an Ig-like fold. This study identified differences between two mutant lamins that cause distinct clinical diseases. One of the <i>LMNA</i> mutations encodes lamin A/C p.R527P and the other codes lamin A/C p.R482W, which are typically associated with muscular dystrophy and lipodystrophy, respectively. To determine how these mutations differentially affect muscle, we generated the equivalent mutations in the <i>Drosophila Lamin C (LamC)</i> gene, an orthologue of human <i>LMNA</i>. The muscle-specific expression of the R527P equivalent showed cytoplasmic aggregation of LamC, a reduced larval muscle size, decreased larval motility, and cardiac defects resulting in a reduced adult lifespan. By contrast, the muscle-specific expression of the R482W equivalent caused an abnormal nuclear shape without a change in larval muscle size, larval motility, and adult lifespan compared to controls. Collectively, these studies identified fundamental differences in the properties of mutant lamins that cause clinically distinct phenotypes, providing insights into disease mechanisms. |
| first_indexed | 2024-03-11T05:09:33Z |
| format | Article |
| id | doaj.art-e0bb11c0fb8a41ef87a20bf88f0c0d91 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T05:09:33Z |
| publishDate | 2023-04-01 |
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| series | Cells |
| spelling | doaj.art-e0bb11c0fb8a41ef87a20bf88f0c0d912023-11-17T18:43:06ZengMDPI AGCells2073-44092023-04-01128114210.3390/cells12081142Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct DiseasesSydney G. Walker0Christopher J. Langland1Jill Viles2Laura A. Hecker3Lori L. Wallrath4Department of Biochemistry and Molecular Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADepartment of Biochemistry and Molecular Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAIndependent Researcher, Gowrie, IA 50543, USADepartment of Biology, Clarke University, Dubuque, IA 52001, USADepartment of Biochemistry and Molecular Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAMutations in the <i>LMNA</i> gene cause a collection of diseases known as laminopathies, including muscular dystrophies, lipodystrophies, and early-onset aging syndromes. The <i>LMNA</i> gene encodes A-type lamins, lamins A/C, intermediate filaments that form a meshwork underlying the inner nuclear membrane. Lamins have a conserved domain structure consisting of a head, coiled-coil rod, and C-terminal tail domain possessing an Ig-like fold. This study identified differences between two mutant lamins that cause distinct clinical diseases. One of the <i>LMNA</i> mutations encodes lamin A/C p.R527P and the other codes lamin A/C p.R482W, which are typically associated with muscular dystrophy and lipodystrophy, respectively. To determine how these mutations differentially affect muscle, we generated the equivalent mutations in the <i>Drosophila Lamin C (LamC)</i> gene, an orthologue of human <i>LMNA</i>. The muscle-specific expression of the R527P equivalent showed cytoplasmic aggregation of LamC, a reduced larval muscle size, decreased larval motility, and cardiac defects resulting in a reduced adult lifespan. By contrast, the muscle-specific expression of the R482W equivalent caused an abnormal nuclear shape without a change in larval muscle size, larval motility, and adult lifespan compared to controls. Collectively, these studies identified fundamental differences in the properties of mutant lamins that cause clinically distinct phenotypes, providing insights into disease mechanisms.https://www.mdpi.com/2073-4409/12/8/1142cardiomyopathy<i>Drosophila</i>Emery–Dreifuss muscular dystrophyfamilial partial lipodystrophyDunnigan typeintermediate filaments |
| spellingShingle | Sydney G. Walker Christopher J. Langland Jill Viles Laura A. Hecker Lori L. Wallrath Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases Cells cardiomyopathy <i>Drosophila</i> Emery–Dreifuss muscular dystrophy familial partial lipodystrophy Dunnigan type intermediate filaments |
| title | Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases |
| title_full | Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases |
| title_fullStr | Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases |
| title_full_unstemmed | Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases |
| title_short | Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases |
| title_sort | drosophila models reveal properties of mutant lamins that give rise to distinct diseases |
| topic | cardiomyopathy <i>Drosophila</i> Emery–Dreifuss muscular dystrophy familial partial lipodystrophy Dunnigan type intermediate filaments |
| url | https://www.mdpi.com/2073-4409/12/8/1142 |
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