rs11558538 — HNMT Thr105Ile

HNMT Thr105Ile - When the Tissue Histamine Enzyme Is Unstable

The Thr105Ile ¹¹ Threonine to isoleucine at position 105 variant (rs11558538) is a well-characterized missense mutation in the HNMT gene that replaces threonine with isoleucine at position 105. Unlike the 3'UTR variant that affects how much enzyme is made, this variant changes the enzyme's structural stability and catalytic efficiency.

The Mechanism

Position 105 lies near the active site of HNMT where SAM and histamine bind. The isoleucine substitution (T allele) destabilizes the protein, leading to faster degradation and lower steady-state enzyme levels in cells. Studies using recombinant HNMT ²² Recombinant protein is produced in laboratory cells to study enzyme properties in isolation from other cellular factors have shown that the Ile105 variant has reduced thermal stability and lower catalytic activity compared to the wild-type Thr105 enzyme. The threonine residue creates a more accessible conformation of substrate binding residues than the isoleucine variant, resulting in higher enzymatic activity.

The Evidence

Preuss et al. (1998)³³ Preuss et al. (1998)
Preuss CV et al. Human Histamine N-Methyltransferase Pharmacogenetics: Common Genetic Polymorphisms That Alter Activity. Mol Pharmacol, 1998 demonstrated that individuals with the TT genotype had significantly lower HNMT enzyme activity in red blood cells. Subsequent studies confirmed that this variant is associated with increased susceptibility to allergic diseases, asthma, and histamine-related symptoms, particularly in European populations. The variant is relatively uncommon in homozygous form (about 2% of Europeans), but heterozygous carriers (about 18%) may experience subtle effects, particularly when combined with other histamine pathway variants. Interestingly, meta-analyses⁴⁴ meta-analyses
Thr105Ile and Parkinson disease meta-analysis have suggested that the Ile105 variant may be associated with reduced risk of Parkinson disease, possibly through altered brain histamine levels.

Brain Histamine

HNMT is the only enzyme that degrades histamine in the brain, where histamine acts as a neurotransmitter ⁵⁵ Brain histamine is released by tuberomammillary neurons in the hypothalamus and helps regulate the sleep-wake cycle involved in wakefulness, appetite, and cognition. Reduced HNMT activity can alter brain histamine signaling, which may partly explain why some individuals with HNMT variants report sleep disturbances, anxiety, or cognitive effects in response to histamine triggers.

Practical Considerations

If you carry the T allele, supporting your methylation pathway (which supplies SAM for HNMT) becomes even more important, since your enzyme is already working at reduced capacity. Combined with DAO variants, this can create a significant histamine clearance deficit that benefits from both dietary management and methylation support.