Journal article
In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies
International journal of molecular sciences, Vol.22(20), p.11226
10/18/2021
DOI: 10.3390/ijms222011226
PMCID: PMC8536974
PMID: 34681887
Abstract
Mutations in the LMNA gene cause diseases called laminopathies. LMNA encodes lamins A and C, intermediate filaments with multiple roles at the nuclear envelope. LMNA mutations are frequently single base changes that cause diverse disease phenotypes affecting muscles, nerves, and fat. Disease-associated amino acid substitutions were mapped in silico onto three-dimensional structures of lamin A/C, revealing no apparent genotype–phenotype connections. In silico analyses revealed that seven of nine predicted partner protein binding pockets in the Ig-like fold domain correspond to sites of disease-associated amino acid substitutions. Different amino acid substitutions at the same position within lamin A/C cause distinct diseases, raising the question of whether the nature of the amino acid replacement or genetic background differences contribute to disease phenotypes. Substitutions at R249 in the rod domain cause muscular dystrophies with varying severity. To address this variability, we modeled R249Q and R249W in Drosophila Lamin C, an orthologue of LMNA. Larval body wall muscles expressing mutant Lamin C caused abnormal nuclear morphology and premature death. When expressed in indirect flight muscles, R249W caused a greater number of adults with wing posturing defects than R249Q, consistent with observations that R249W and R249Q cause distinct muscular dystrophies, with R249W more severe. In this case, the nature of the amino acid replacement appears to dictate muscle disease severity. Together, our findings illustrate the utility of Drosophila for predicting muscle disease severity and pathogenicity of variants of unknown significance.
Details
- Title: Subtitle
- In Silico and In Vivo Analysis of Amino Acid Substitutions That Cause Laminopathies
- Creators
- Benjamin E Hinz - University of IowaSydney G Walker - University of IowaAustin Xiong - University of IowaRose A Gogal - University of IowaMichael J Schnieders - University of IowaLori L Wallrath - University of Iowa
- Resource Type
- Journal article
- Publication Details
- International journal of molecular sciences, Vol.22(20), p.11226
- DOI
- 10.3390/ijms222011226
- PMID
- 34681887
- PMCID
- PMC8536974
- NLM abbreviation
- Int J Mol Sci
- ISSN
- 1422-0067
- eISSN
- 1422-0067
- Grant note
- DOI: 10.13039/100000069, name: National Institute of Arthritis and Musculoskeletal and Skin Diseases, award: R21AR075193; name: National Institute of Health, award: 2T32GM008365-26A 1, R01DC012049, N/A, N/A; DOI: 10.13039/100012675, name: Center for Biocatalysis and Bioprocessing, award: N/A
- Language
- English
- Date published
- 10/18/2021
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Biochemistry and Molecular Biology; Chemical and Biochemical Engineering; University College Courses
- Record Identifier
- 9984196983402771
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