Chowanadisai W (2014), Comparative genomic analysis of slc39a12/ZIP12:...

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PLoS One 2014 Nov 06;911:e111535. doi: 10.1371/journal.pone.0111535.

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Comparative genomic analysis of slc39a12/ZIP12: insight into a zinc transporter required for vertebrate nervous system development.

Chowanadisai W .

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The zinc transporter ZIP12, which is encoded by the gene slc39a12, has previously been shown to be important for neuronal differentiation in mouse Neuro-2a neuroblastoma cells and primary mouse neurons and necessary for neurulation during Xenopus tropicalis embryogenesis. However, relatively little is known about the biochemical properties, cellular regulation, or the physiological role of this gene. The hypothesis that ZIP12 is a zinc transporter important for nervous system function and development guided a comparative genetics approach to uncover the presence of ZIP12 in various genomes and identify conserved sequences and expression patterns associated with ZIP12. Ortholog detection of slc39a12 was conducted with reciprocal BLAST hits with the amino acid sequence of human ZIP12 in comparison to the human paralog ZIP4 and conserved local synteny between genomes. ZIP12 is present in the genomes of almost all vertebrates examined, from humans and other mammals to most teleost fish. However, ZIP12 appears to be absent from the zebrafish genome. The discrimination of ZIP12 compared to ZIP4 was unsuccessful or inconclusive in other invertebrate chordates and deuterostomes. Splice variation, due to the inclusion or exclusion of a conserved exon, is present in humans, rats, and cows and likely has biological significance. ZIP12 also possesses many putative di-leucine and tyrosine motifs often associated with intracellular trafficking, which may control cellular zinc uptake activity through the localization of ZIP12 within the cell. These findings highlight multiple aspects of ZIP12 at the biochemical, cellular, and physiological levels with likely biological significance. ZIP12 appears to have conserved function as a zinc uptake transporter in vertebrate nervous system development. Consequently, the role of ZIP12 may be an important link to reported congenital malformations in numerous animal models and humans that are caused by zinc deficiency.

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Species referenced: Xenopus tropicalis
Genes referenced: slc39a12 slc39a4

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	Figure 2. Phylogenetic alignment and nucleotide sequences of slc39a12 show conservation across vertebrates.Human slc39a12 gene structure is indicated. Multiz phylogenetic alignment of slc39a12 orthologs in 16 vertebrate genomes show conservation in exons and some extra-exonic regions. Primate and vertebrate exonic and intronic regions of conservation are indicated by peaks following analysis by PhyloP and PhastCons. Scale bar at top indicates 50 kb.
	Figure 3. Synteny of slc39a12 is preserved across nearly all vertebrates examined.Xenopus refers to tropicalis species of frog. NCBI accession numbers are indicated in parentheses where slc39a12 is present. Gaps between solid lines within the same chromosome indicate that genes may be distant from each other. Chromosome number (Ch) is noted to indicate chromosome location of genes. The asterisk indicates that the putative slc39a12 gene in Caenorhabditis elegans could not be confirmed using reciprocal BLAST hits.
	Figure 4. Phylogenetic tree based upon ZIP12 amino acid sequences in different species.Common names of organisms are listed. Scale bar indicates 0.2 amino acid substitutions per site.
	Figure 5. Alignment for 5â² UTR, first 90 bp of coding region, and the proximal promoter (1000 bp upstream of transcription start site) of human, mouse, and cow slc39a12.Lowercase and uppercase in sequences indicate nucleotide and amino acid sequences, respectively. Black shaded text indicates possible transcription factor binding sites in largely conserved regions. Gray shaded text indicates 5â² UTR. For coding regions, possible signal peptide is underlined. Asterisks indicate nucleotides conserved in all sequences following alignment.
	Figure 6. Rat slc39a12 mRNA and translated protein sequences derived from EST and genome analyses.Full sequence was formed from rat EST [GenBank: FM065041], genome sequence [GenBank: NW_047496, nucleotides 3955687-3955698], and current annotated entry for rat slc39a12 [GenBank: NM_001106124]. The additional N-terminus amino acid sequence is shaded gray. Stop codon (opal) upstream of putative start codon is shaded black.
	Figure 7. Histidine-rich exon 9 present in human and mouse ZIP12 is also present in cow, opossum, and chicken genomes.Organism common names are accompanied by accession numbers, corresponding nucleotides, and translated amino acid sequence. Amino acids conserved between humans and mice are shaded in black. Corresponding amino acids that are conserved in cow, opossum, and chicken are shaded in grey.
	Figure 8. Splice variation of ZIP12 confirmed in the brain of multiple species.Different splice variants of ZIP12 are present in (A) humans, (B) cow, and (C) rat, but the short variant is not detectable in (D) mice. PCR was conducted on cDNA reverse-transcribed from polyadenylated or ZIP12-specific RNA using primers spanning the exon that is present and absent in the long and short isoform, respectively. The corresponding molecular weights of the DNA markers are indicated.
	Figure 9. Amino acid alignment of ZIP12 demonstrates splice variation due to variable inclusion of a exon which contains a histidine-rich motif.Where indicated, -1 and -2 indicate annotated entries for splice variants of ZIP12 from inclusion or exclusion of exon 9. Shown alignment performed by ClustalW corresponds to amino acids 464â523 of the longer human ZIP12 variant (Human-2) [GenBank: NP_001138667]. Conserved histidine residues are shaded in black. Asterisks indicate organisms with a single annotated amino acid sequence for ZIP12 that lacks exon 9. Full sequence alignment is provided in Figure S3.
	Figure 1. Human slc39a12 gene structure.Exon-intron structure drawn to approximate scale. Exon 2 (shaded gray) contains the translation start codon. Exon 9 (shaded black) contains a variable exon depending on splice variation that leads to exon inclusion or exclusion. Exon 13 (striped) contains the stop codon (ochre). The exon structure (number of exons, relative exon size) of slc39a12 is conserved in mice and Xenopus tropicalis.

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