The Human OCTN Sub-Family: Gene and Protein Structure, Expression, and Regulation

Abstract

OCTN1 and OCTN2 are membrane transport proteins encoded by the SLC22A4 and SLC22A5 genes, respectively. Even though several transcripts have been predicted by bioinformatics for both genes, only one functional protein isoform has been described for each of them. Both proteins are ubiquitous, and depending on the physiopathological state of the cell, their expression is regulated by well-known transcription factors, although some aspects have been neglected. A plethora of missense variants with uncertain clinical significance are reported both in the dbSNP and the Catalogue of Somatic Mutations in Cancer (COSMIC) databases for both genes. Due to their involvement in human pathologies, such as inflammatory-based diseases (OCTN1/2), systemic primary carnitine deficiency (OCTN2), and drug disposition, it would be interesting to predict the impact of variants on human health from the perspective of precision medicine. Although the lack of a 3D structure for these two transport proteins hampers any speculation on the consequences of the polymorphisms, the already available 3D structures for other members of the SLC22 family may provide powerful tools to perform structure/function studies on WT and mutant proteins.

Keywords: IBD; OCTN1; OCTN2; SLC22 family; carnitine; gene expression and regulation.

Figure 1

SLC22A4 gene map. The exons and UTRs are indicated as red and grey squares, respectively. The size of each square is proportional to its length.

Figure 2

Distribution of polymorphisms on the SLC22A4 homology model obtained as described in [9]. (a) The positions not affected by polymorphisms are indicated as white ribbons. The amino acids, which have been found mutated in one, two, three, or four other different amino acids, are indicated in yellow, orange, blue, and cyan, respectively. The two target amino acids of the organic cation and zwitterion binding sites are indicated in red and green, respectively. (b) Zoom in on the putative substrate binding sites with the amino acids within 4 Å colored as in (a).

Figure 3

Somatic mutations of the OCTN1 gene in cancer.

Figure 4

Distribution of somatic mutations in cancer on the SLC22A4 homology model obtained as described in [9]. (a)The amino acids that have been found mutated in one, two, or three different other amino acids are indicated in yellow, orange, and blue, respectively. The two target amino acids of the organic cation and zwitterion putative binding sites are indicated in red and green, respectively. (b) Zoom in on the substrate binding sites with the amino acids within 4 Å colored as in (a).

Figure 5

OCTN1 promoter/enhancer scheme. The experimentally proven and bioinformatically predicted features are indicated in blue and purple, respectively. The corresponding regions are described in the text. The predicted transcription factors of Table 1 are also shown.

Figure 6

Tissue expression profile of the SLC22A4 RNA; nTPM, normalized transcript per million, adapted from https://www.proteinatlas.org/ENSG00000197208-SLC22A4/tissue#rna_expression (accessed on 20 June 2024).

Figure 7

SLC22A5 gene map. The exons and UTRs are indicated as red and grey squares, respectively. The size of each square is proportional to its real length. The additional exon of the OCTN2 isoform 1 is shown in green. The size of each square is proportional to its length. ERE: estrogen-responsive element.

Figure 8

Ribbon representation of the 1–523 aa of the OCTN2 homology model retrieved from AlphaFold database. The loss of function variants protruding into the translocation pore are highlighted as yellow licorices.

Figure 9

Somatic mutations of the OCTN2 gene in cancer.

Figure 10

OCTN2 promoter/enhancer scheme. The experimentally proven and the bioinformatically predicted features are indicated in blue and purple, respectively. The corresponding regions are described in the text. The predicted transcription factors of Table 3 and the lncRNA MIR3936HG are also shown.

Figure 11

Tissue expression profile of the SLC22A5 RNA. nTPM, normalized transcript per million, adapted from https://www.proteinatlas.org/ENSG00000197375-SLC22A5/tissue#rna_expression (accessed on 20 June 2024).