Background: A considerable proportion of the symptoms associated with excessive dietary
intake can be attributed to systemic imbalances in lipid metabolism. The prominent
toxicity of saturated fatty acids has been repeatedly demonstrated and sheds light
on the protective role of stearoyl-CoA desaturase-1 (SCD1), the key enzyme for fatty
acid desaturation. SCD1 protein expression is regulated at the levels of transcription,
translation, and degradation. However, the modulating effect of the variability of
the human genome must also be taken into account. Therefore, we aimed to ascertain
whether natural missense or frameshift mutations in SCD1 (p.H125P, p.M224L, p.A333T,
p.R253AfsTer7) could influence the expression, degradation, or function of the enzyme.
Methods: In silico and in vitro experiments were conducted to comprehensively evaluate
the consequences associated with each genetic variation, with the objective of using
the results to propose a risk or severity ranking of SCD1 variants. Results: As anticipated,
the p.R253AfsTer7 variant was identified as the most deleterious in structural, functional,
and quantitative terms. The p.H125P variant also reduced the desaturation capacity
of the enzyme in accordance with the predicted structural alterations and augmented
degradation resulting from folding complications. This was aggravated by increased
mRNA instability and accompanied by mild endoplasmic reticulum stress induction. The
p.A333T protein exhibited an intermediate phenotype, whereas p.M224L showed no deleterious
effects and even increased the amount of SCD1. Conclusions: In conclusion, the large-scale
identification of genetic variations needs to be supplemented with comprehensive functional
characterization of these variations to facilitate adequate personalized prevention
and treatment of lipid metabolism-related conditions.
