*4.4. Class 2 Mutations*

Further embracing the CFTR classification, the next group of mutations (Class 2) consists of genetic alterations, usually mild mutations or polymorphisms, which result in a protein with impaired trafficking to the cell surface, while possessing more or less preserved transport function (recently reviewed in [137]). A typical of Class 2 variants is Q141K (rs2231142), which is the most frequent genetic variant of ABCG2 other than wild type. Its allele frequency is the highest in Southwest Asia (MAF values are between 0.222 and 0.319), whereas it is less common in the Caucasian populations (MAF = 0.107–0.119) and is rather rare in Africa (MAF = 0.009) [115,116]. Because of its frequency and its association with gout (see Section 6.1), ABCG2-Q141K is the most broadly studied variant of ABCG2. It has major folding and trafficking problems, undergoes partial degradation, thus exhibiting reduced overall and cell surface expression [32,33,95,100,115,117,118].

Using a flow cytometry-based screening method for reduced ABCG2 expression in RBCs, we have recently identified a polymorphic variant (M71V) with a character similar to that of Q141K [112,120]. The rare F373C missense mutation also belongs to this group, as the substrate stimulated ATPase activity and the specific transport activity of ABCG2-F373 are preserved, but its cell surface expression is diminished [104].

It should be noted that in most cases, not only the trafficking but also the transport function is affected by these mutations to certain extent. Nevertheless, they are classified into this group, because the defect caused by these mutations can—at least partially—be corrected by pharmacological chaperones (or correctors), whereas application of correctors for other types of mutations is usually unreasonable. The different approaches to rescue the various phenotypes will be discussed later.
