Polymorphism functional studies

Mitomo H, Kato R, Ito A, et al. A functional study on polymorphism of the ATP-binding cassette transporter ABCG2 critical role of arginine-482 in methotrexate transport. Biochem J 2003 373 767-774. 

Three major types of evidence are needed to imphcate a polymorphism in chnical care screens of tissues from multiple humans linking the polymorphism to a trait complementary preclinical functional studies indicating that the polymorphism is plausibly linked with the phenotype and multiple supportive clinical phenotype/genotype studies. Because of the high probability of error in genotype/phenotype association studies, replication is essential. 

Britton We have identified a number of loss-of-function polymorphisms in this gene, but these alleles must be of sufficient frequency for use in association studies. It has been helpful to have an in vitro model to help select which polymorphisms to study at a population level. 

As yet, no human diseases have been identified as a result of FATPl mutations. However, genetic polymorphisms in the human FATPl gene have been linked to dyslipidemia. An A/G exchange at position +48 in intron 8 of the FATPl gene has been shown to result in increased TG concentrations in female but not in male subjects. In a second study, the same polymorphism was linked to increased postprandial TG concentrations and smaller low density lipoprotein (LDL) particles. To date, it is still unknown if this polymorphism is associated with altered levels of FATPl expression and/or function. 

Moreover, there exist polymorphic MOP variants. An Asn40Asp polymorphism has been found with a high abundance in the Caucasian and Asian population. This receptor variant is less expressed in the brain and carrier of this polymorphism appears to need more opioids for analgesic treatment. There are many additional MOP polymorphisms with unknown functional significance. In spite of many studies there appears to exist no significant association of polymorphisms in the MOP gene and drug addiction [5]. 

Progress in molecular biology has provided a new perspective. Techniques such as the polymerase chain reaction and single-strand conformation polymorphism analysis have greatly facilitated the molecular analysis of erythroenzymopathies. These studies have clarified the correlation between the functional and structural abnormalities of the variant enzymes. In general, the mutations that induce an alteration of substrate binding site and/or enzyme instability might result in markedly altered enzyme properties and severe clinical symptoms. 

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