Beyond membrane channelopathies: alternative mechanisms underlying complex human disease

Area of Science:

• Molecular biology
• Human genetics
• Cellular physiology

Background:

• Advances in understanding human disease mechanisms have been driven by discoveries of gene mutations affecting membrane ion channels and transporters.
• Ion channel defects, or channelopathies, are linked to diverse conditions like cystic fibrosis, cardiac arrhythmias, diabetes, skeletal muscle disorders, and neurological conditions.
• Emerging evidence indicates that diseases, especially in excitable cells, can also stem from defects in non-ion channel proteins located beneath the plasma membrane.

Purpose of the Study:

• To review the role of lamins in human disease.
• To highlight the expanding understanding of molecular mechanisms underlying human diseases beyond ion channelopathies.
• To discuss novel insights into disease pathogenesis provided by studying gene products like lamins.

Main Methods:

• Literature review of recent research on gene mutations and human diseases.
• Analysis of studies linking non-ion channel proteins to specific disease phenotypes.
• Focus on the role of lamins as a class of gene products implicated in disease.

Main Results:

• Ion channel defects are established causes of various human diseases.
• A new category of potentially fatal cardiac arrhythmias is associated with cytoplasmic proteins (e.g., ankyrin-B, ankyrin-G, alpha-1 syntrophin, caveolin-3, yotiao, GPD1L).
• Lamins represent another class of gene products offering new perspectives on human disease.

Conclusions:

• Human diseases, particularly those affecting excitable cells, can arise from defects in a broader range of cellular components than previously recognized.
• The study of non-ion channel proteins, such as lamins, is crucial for a comprehensive understanding of disease etiology.
• Lamins provide elegant new insights into the molecular underpinnings of human disease.