Klotho gene variation and expression in 20 inbred mouse strains

Area of Science:

• Genetics
• Aging Research
• Molecular Biology

Background:

• Defects in klotho gene expression in mice mimic human aging syndromes, including shortened lifespan, arteriosclerosis, and hearing loss.
• The klotho gene encodes secreted and membrane-bound isoforms crucial for cellular function and aging regulation.

Purpose of the Study:

• To identify functional murine variants of the klotho gene.
• To examine the renal expression of klotho isoforms in different mouse strains.
• To investigate the correlation between klotho gene variants and aging-related phenotypes.

Main Methods:

• Sequencing of the klotho gene across 16 laboratory-derived and 4 wild-derived inbred mouse strains.
• Analysis of renal klotho gene expression for both secreted and membrane-bound isoforms.
• Identification and characterization of sequence variations, including amino acid substitutions.

Main Results:

• No sequence variations were found in laboratory-derived strains.
• Forty-five sequence variants, including six amino acid substitutions, were identified in wild-derived strains.
• The SPRET/Ei wild-derived strain exhibited four amino acid substitutions and increased membrane klotho mRNA levels.
• An elevated membrane to secreted klotho expression ratio was observed in three wild-derived strains with klotho gene mutations.
• SPRET/Ei mice demonstrated longer lifespans, reduced atherosclerosis risk factors, and improved hearing compared to other strains.

Conclusions:

• Wild-derived mouse strains harbor significant klotho gene sequence variations.
• Specific klotho gene variants, particularly in the SPRET/Ei strain, are associated with improved aging phenotypes.
• These findings highlight the role of klotho gene diversity in modulating aging processes and related health outcomes.