Comparison of protein structural model of ABCC2Ser1342Tyr mutation
ABCC2 have consisted of 32 exons involved in bile formation which
mediates hepatobiliary excretion of numerous organic anions and
conjugated organic anions such as methotrexate and also transports
sulfated bile salt such as taurolithocholate
sulfate.20,
21 This gene has two main nucleotide
binding domains which located at position 671-678 and 1334-1341 (Figure
2A), separately. This location of this variant (Ser1342Tyr) in this
study is closely to the ATP binding functional domain (1334-1341).
To further investigate the possible effects of the missense variant on
protein structure, the reference and the modified protein structure ofABCC2 gene were compared simultaneously using UCSF Chimera
1.14rc. The result showed that, compared reference molecular structure,
the 3D model of mutation have a slight change in the chemical bond
lengths of ATP-ligand binding amino acid side chains at positions
Ser1342, Ser678 and Gln706 (Figure 2B). The change in the amino side
chains could affect the binding efficiency of the ATP molecular.
To further analysis the genetic basis of ABCC2 , we analyzed the
mRNA expression level of ABCC2 gene in placental tissue between 2
healthy and four ICP patients using the GEO datasets derived from NCBI
(GEO accession: GSE46157), when having no liver targeted tissue. The
significant (P < 0.05) difference in the gene
expression was observed between the two groups (Figure 2C). And the
expression of ABCC2 upregulated in ICP group. Besides, we also
detected that the expression of other three genes, such as ABCC6 ,ABCE1 and ABCG5 , have changed in placental tissue (See
Supplementary material, Figure S4).