Single-Nucleotide Polymorphism of the MLX Gene Is Associated With Takayasu Arteritis

by Selleckchem | Nov 06 2023

Background: Takayasu arteritis (TAK) is an autoimmune systemic arteritis of unknown pathogenesis. Genome-wide association studies revealed that single-nucleotide polymorphisms in the MLX gene encoding the MLX (Max-like protein X) transcription factor are significantly associated with TAK in Japanese patients. MLX single-nucleotide polymorphism rs665268 is a missense mutation causing the Q139R substitution in the DNA-binding site of MLX.

Methods: To elucidate the hypothesis that the single-nucleotide polymorphism of the MLX gene plays a critical role in the development of TAK, we conducted clinical and laboratory analyses.

Results: We show that rs665268 significantly correlated with the severity of TAK, including the number of arterial lesions and morbidity of aortic regurgitation; the latter may be attributed to the fact that MLX mRNA expression was mostly detected in the aortic valve. Furthermore, the Q139R mutation caused structural changes in MLX, which resulted in enhanced formation of a heterodimer with MondoA, upregulation of TXNIP (thioredoxin-interacting protein) expression, and increase in the activity of the NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome and cellular oxidative stress. Furthermore, autophagy, which negatively regulates inflammasome activation, was suppressed by the Q139R mutation in MLX. The MLX-Q139R mutant significantly induced macrophage proliferation and macrophage-endothelium interaction, which was abolished by the treatment with SBI-477, an inhibitor of MondoA nuclear translocation. Our findings suggest that the Q139R substitution in MLX plays a crucial role in the pathogenesis of TAK.

Conclusions: MLX-Q139R mutation plays a crucial role in the pathogenesis of TAK through promoting inflammasome formation.

Comments:

The research described in your background and methods section suggests that a specific mutation in the MLX gene, known as rs665268 or the Q139R mutation, is significantly associated with Takayasu arteritis (TAK) and plays a critical role in its development. Takayasu arteritis is an autoimmune disease characterized by systemic arteritis of unknown cause.

The study conducted clinical and laboratory analyses to investigate the hypothesis that the MLX gene mutation contributes to the development of TAK. The results showed a significant correlation between the MLX gene mutation and the severity of TAK, including the number of arterial lesions and the morbidity of aortic regurgitation. The expression of MLX mRNA was primarily detected in the aortic valve, which may explain the association with aortic regurgitation.

The Q139R mutation in MLX resulted in structural changes in the MLX protein. This led to enhanced formation of a heterodimer with MondoA, increased expression of TXNIP (thioredoxin-interacting protein), and heightened activity of the NLRP3 inflammasome and cellular oxidative stress. The Q139R mutation also suppressed autophagy, which negatively regulates inflammasome activation.

Furthermore, the MLX-Q139R mutant induced macrophage proliferation and macrophage-endothelium interaction. However, these effects were abolished when treated with SBI-477, an inhibitor of MondoA nuclear translocation. This suggests that the interaction between MLX-Q139R and MondoA is crucial for the observed cellular changes in TAK.

In conclusion, the study provides evidence that the MLX-Q139R mutation plays a significant role in the pathogenesis of Takayasu arteritis. It promotes inflammasome formation, resulting in increased inflammation, oxidative stress, and impaired autophagy. These findings contribute to our understanding of the underlying mechanisms involved in TAK development and may help in developing targeted therapies for the disease.