Loss-of-Function Mutations in the Human Luteinizing Hormone Receptor Predominantly Cause Intracellular Retention

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Mutations in G protein-coupled receptors (GPCRs), such as the luteinizing hormone receptor (LHR), are linked to endocrine hormone signaling deficiencies.
• Inactivating GPCR mutations can disrupt ligand binding, receptor activation, signaling pathways, or cause misfolding and reduced cell surface expression.

Purpose of the Study:

• To investigate the functional consequences of various mutant human LHRs identified in patients with reproductive dysfunction.
• To determine the specific molecular defects (ligand binding, signaling, cell surface expression) caused by these LHR mutations.

Main Methods:

• Analysis of cell surface expression levels of mutant LHRs.
• Assessment of ligand binding affinity for mutant LHRs.
• Evaluation of signaling pathway activation by mutant LHRs.

Main Results:

• The majority of LHR mutations (14/20) resulted in significantly reduced cell surface expression, indicating intracellular retention.
• Two mutations impaired ligand binding affinity, and two mutations affected signaling.
• Two mutations showed no discernible impairment of receptor function.

Conclusions:

• Most disease-associated LHR mutations impair function primarily through intracellular retention, rather than defects in binding or signaling.
• These findings underscore the diverse mechanisms by which GPCR mutations cause dysfunction.
• The results suggest a therapeutic potential for pharmacological chaperones to rescue the expression and function of retained mutant GPCRs.