Abstract
Background: The MTUS1 gene encodes a microtubule-associated protein involved in multiple processes including cell polarity and microtubule balance during myocardial development.Aims: To investigate the association between a de novo c. 2617A->C mutation in MTUS1 (NM_001001924.2) and non-compaction of ventricular myocardium (NVM) and explore the potential mechanisms.Methods: A de novo mutation in MTUS1 was identified for a familial pedigree with NVM. Lentiviral vectors containing MTUS1 wild type or the mutation MTUS1 were constructed and co-infected into HEK-293 cells. MTUS1, Rac1/Cdc42, α-tubulin, α/β-tubulin, polarity protein (PAR6), and the morphology of daughter cells were measured by real-time PCR, Western blot, and immunofluorescence assays, respectively.Results: The lentiviral vectors were constructed successfully. Immunofluorescence assays revealed the fluorescence intensity of α-tubulin to be decreased and α/β-tubulin to be increased in the mutation MTUS1 group. The fluorescence intensity of PAR6 was higher and morphology of the daughter cells in the mutation group was different from the wild type group. The phosphorylation of Rac1/Cdc42 in the mutation group was significantly lower than in the wild type group.Conclusions: A de novo mutation in MTUS1 decreased the stability of microtubules and increased cell polarity via the Rac1/Cdc42 pathway, which may partly elucidate the mechanism underlying cellular protection in NVM.
Highlights
Non-compaction of ventricular myocardium (NVM) is a structural abnormality of the left ventricular myocardium that is accompanied by severe clinical symptoms and a poor prognosis with no currently available effective prevention and therapeutic methods [1,2,3,4]
In schematic representation of the human Microtubule-associated tumor suppressor 1 (MTUS1) gene, the site of c. 2617A->C mutation located in exon 6, and in structural organization of ATIP3 protein, the position of the mutant amino-acid sequence was in D2 (Figure 1E), which decorates and stabilizes microtubules [22]
It indicated that the mutant localized to an important functional domain. This mutation was present in the two sisters affected by NVM but absent from their mother and aunt. It means that a correlation between the NVM phenotype and the c. 2617A->C mutation was discovered in this NVM family
Summary
Non-compaction of ventricular myocardium (NVM) is a structural abnormality of the left ventricular myocardium that is accompanied by severe clinical symptoms and a poor prognosis with no currently available effective prevention and therapeutic methods [1,2,3,4]. Microtubules are a component of the cytoskeleton, found in eukaryotic cells, and formed by the polymerization of a dimer of two globular proteins, α, and β tubulin. These tubular polymers of tubulin are highly dynamic and stabilize the cell structure, transport intracellular substances, and mediate cell movement. Disruption of the cell polarity complex by targeted gene mutations results in aberrant mitotic spindles, loss of polarized cardiomyocyte division, and loss of normal myocardial trabeculation [9]. The MTUS1 gene encodes a microtubule-associated protein involved in multiple processes including cell polarity and microtubule balance during myocardial development
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