A human infertility-associated KASH5 variant promotes mitochondrial localization.

Area of Science:

• Cell Biology
• Genetics
• Reproductive Biology

Background:

• KASH5 is a protein of the outer nuclear membrane (ONM) and endoplasmic reticulum (ER) essential for homologous chromosome pairing during meiosis.
• A KASH5 variant (L535Q) has been associated with male infertility and azoospermia, but the underlying molecular mechanism remains unclear.

Purpose of the Study:

• To elucidate the molecular mechanism by which the L535Q KASH5 variant leads to male infertility and azoospermia.
• To investigate the impact of the L535Q substitution on KASH5 protein localization and function.

Main Methods:

• Analysis of the L535Q substitution within the KASH5 transmembrane domain (TMD) using hydrophobicity scales (GES).
• Amino acid substitution studies to assess the effects on KASH5 subcellular localization.
• Investigated localization to the ER, ONM, and mitochondrial membranes.

Main Results:

• The L535Q substitution reduces the hydrophobicity of the KASH5 TMD.
• This change in hydrophobicity causes KASH5 to mislocalize from the ER and ONM to the mitochondrial membrane.
• The L535Q substitution perturbs normal KASH5 localization.

Conclusions:

• The L535Q KASH5 variant's mislocalization to mitochondria disrupts its function in nuclear envelope-chromosome interactions.
• This mistargeting provides a molecular explanation for the observed male infertility and azoospermia phenotype in patients carrying the L535Q variant.