Human histamine N-methyltransferase pharmacogenetics: common genetic polymorphisms that alter activity

Area of Science:

• Pharmacogenomics
• Human Genetics
• Enzymology

Background:

• Histamine N-methyltransferase (HNMT) is crucial for histamine metabolism.
• HNMT activity levels in humans are genetically determined.
• Understanding the molecular basis of this genetic regulation is essential.

Purpose of the Study:

• To investigate the molecular basis of genetic regulation of HNMT activity.
• To identify genetic polymorphisms in the HNMT gene and their functional consequences.

Main Methods:

• Northern blot analysis to determine HNMT expression in human kidneys.
• Enzyme activity and thermal stability assays on 127 renal biopsy samples.
• Polymerase chain reaction (PCR) amplification and sequencing of HNMT gene exons.
• Genotyping of 114 samples for identified C314T and A939G polymorphisms.
• Transient expression studies in COS-1 cells to validate functional impact.

Main Results:

• HNMT is highly expressed in the kidney.
• Two key polymorphisms identified: C314T (Thr105Ile) and A939G (3'-UTR).
• Allele frequencies: Thr105 (0.90), Ile105 (0.10); A939 (0.79), G (0.21).
• Ile105 allele associated with significantly lower HNMT activity and thermal stability.
• Transient expression confirmed lower activity and protein levels for Ile105 variant.

Conclusions:

• Genetic polymorphisms in HNMT, specifically the Ile105 variant, lead to reduced enzyme activity and stability.
• These findings provide a molecular basis for inherited differences in HNMT activity.
• The study supports the hypothesis that HNMT genetic variations may contribute to human disease pathophysiology.