In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies

Hinz, Benjamin E.; Walker, Sydney G.; Xiong, Austin; Gogal, Rose A.; Schnieders, Michael J.; Wallrath, Lori L.

doi:10.3390/ijms222011226

Cited by 9 publications

(18 citation statements)

References 83 publications

(152 reference statements)

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“…The positions of the amino acid changes examined in this study are shown with the corresponding human amino acid changes in parentheses. (B) Three-dimensional model of full-length human lamin A ( Hinz et al, 2021 ) with the position of the amino acid changes in the head and rod domain indicated by arrows. The positions of amino acid changes in the Ig fold are indicated in the magnified view (panel C).…”

Section: Resultsmentioning

confidence: 99%

“…The amino acid changes under investigation were mapped onto the three-dimensional structure of lamin A/C that is based on a combination of experimental data and in silico predictions ( Figure 1B ) ( Krimm et al, 2002 ; Strelkov et al, 2004 ; Lilina et al, 2020 ; Hinz et al, 2021 ). The amino acid residues S22 and K32 map within a short-predicted alpha-helical region of the head domain ( Figure 1B ).…”

Section: Resultsmentioning

confidence: 99%

“…Colors correspond to the protein domain where the amino acid change is located: head (red), rod (blue), and tail (green). Frontiers in Cell and Developmental Biology frontiersin.org Hinz et al, 2021). The amino acid residues S22 and K32 map within a short-predicted alpha-helical region of the head domain (Figure 1B).…”

Section: Drosophila Larval Body Wall Musclespecific Expression Of Mut...mentioning

confidence: 98%

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Effects of mutant lamins on nucleo-cytoskeletal coupling in Drosophila models of LMNA muscular dystrophy

Shaw

Rios-Monterrosa

Fedorchak

et al. 2022

Front. Cell Dev. Biol.

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The nuclei of multinucleated skeletal muscles experience substantial external force during development and muscle contraction. Protection from such forces is partly provided by lamins, intermediate filaments that form a scaffold lining the inner nuclear membrane. Lamins play a myriad of roles, including maintenance of nuclear shape and stability, mediation of nuclear mechanoresponses, and nucleo-cytoskeletal coupling. Herein, we investigate how disease-causing mutant lamins alter myonuclear properties in response to mechanical force. This was accomplished via a novel application of a micropipette harpooning assay applied to larval body wall muscles of Drosophila models of lamin-associated muscular dystrophy. The assay enables the measurement of both nuclear deformability and intracellular force transmission between the cytoskeleton and nuclear interior in intact muscle fibers. Our studies revealed that specific mutant lamins increase nuclear deformability while other mutant lamins cause nucleo-cytoskeletal coupling defects, which were associated with loss of microtubular nuclear caging. We found that microtubule caging of the nucleus depended on Msp300, a KASH domain protein that is a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex. Taken together, these findings identified residues in lamins required for connecting the nucleus to the cytoskeleton and suggest that not all muscle disease-causing mutant lamins produce similar defects in subcellular mechanics.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Drosophila Larval Body Wall Musclespecific Expression Of Mut...mentioning

confidence: 98%

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Effects of mutant lamins on nucleo-cytoskeletal coupling in Drosophila models of LMNA muscular dystrophy

Shaw

Rios-Monterrosa

Fedorchak

et al. 2022

Front. Cell Dev. Biol.

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“…Over 400 mutations in LMNA have been linked to diseases collectively called laminopathies, the majority affecting muscle [ 28 , 29 , 30 ]. Most LMNA DNA lesions are point mutations that give rise to single amino acid substitutions throughout the head, rod, and tail domain, which possess an Ig-like fold [ 31 , 32 ]. Several studies have attempted to establish a correlation between the genotype and disease phenotype; however, such correlations are limited [ 6 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases

Walker

Langland

Viles³

et al. 2023

Cells

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Mutations in the LMNA gene cause a collection of diseases known as laminopathies, including muscular dystrophies, lipodystrophies, and early-onset aging syndromes. The LMNA 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 LMNA 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 Drosophila Lamin C (LamC) gene, an orthologue of human LMNA. 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.

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“…Lamin A consists of a 42‐residue lamin‐specific 1B insert and constitutes almost half of the super‐helix turn in the middle of the 1B domain, with which it preserves heptad periodicity for dimer formation, conserves the positions of the distal coiled‐coil regions for tetramer formation, and provides additional interdimer molecular contacts 6–9 . Thus, mutations in the rod domain of lamin A could directly affect intermolecular interactions and/or protein stability, and may lead to progeroid laminopathies such as APS and A‐WS 9,10 …”

Section: Introductionmentioning

confidence: 99%

Mice harboring a R133L heterozygous mutation in LMNA exhibited ectopic lipid accumulation, aging, and mitochondrial dysfunction in adipose tissue

et al. 2022

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The LMNA gene encodes for the nuclear envelope proteins lamin A and C (lamin A/C). A novel R133L heterozygous mutation in the LMNA gene causes atypical progeria syndrome (APS). However, the underlying mechanism remains unclear. Here, we used transgenic mice (LmnaR133L/+ mice) that expressed a heterozygous LMNA R133L mutation and 3T3‐L1 cell lines with stable overexpression of LMNA R133L (by lentiviral transduction) as in vivo and in vitro models to investigate the mechanisms of LMNA R133L mutations that mediate the APS phenotype. We found that a heterozygous R133L mutation in LMNA induced most of the metabolic disturbances seen in patients with this mutation, including ectopic lipid accumulation, limited subcutaneous adipose tissue (SAT) expansion, and insulin resistance. Mitochondrial dysfunction and senescence promote ectopic lipid accumulation and insulin resistance. In addition, the FLAG‐mediated pull‐down capture followed by mass spectrometry assay showed that p160 Myb‐binding protein (P160 MBP; Mybbp1a$$ a $$), the critical transcriptional repressor of PGC‐1α, was bound to lamin A/C. Increased Mybbp1a$$ a $$ levels in tissues and greater Mybbp1a$$ a $$‐lamin A/C binding in nuclear inhibit PGC‐1α activity and promotes mitochondrial dysfunction. Our findings confirm that the novel R133L heterozygous mutation in the LMNA gene caused APS are associated with marked mitochondrial respiratory chain impairment, which were induced by decreased PGC‐1α levels correlating with increased Mybbp1a levels in nuclear, and a senescence phenotype of the subcutaneous fat.

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In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies

Cited by 9 publications

References 83 publications

Effects of mutant lamins on nucleo-cytoskeletal coupling in Drosophila models of LMNA muscular dystrophy

Effects of mutant lamins on nucleo-cytoskeletal coupling in Drosophila models of LMNA muscular dystrophy

Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases

Mice harboring a R133L heterozygous mutation in LMNA exhibited ectopic lipid accumulation, aging, and mitochondrial dysfunction in adipose tissue

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