TMEM169

The gene is located on human chromosome 2(2q35) and spans 20,918 bases (216,081,866-216,102,783)[8] on the + strand. The gene contains four exons in total. The direct neighbors of TMEM169 include XRCC5 (X-ray repair cross complementing 5) and PECR (peroxisomal trans-2-enoyl-CoA reductase).[1]

There are two transmembrane domains of Homo sapiens TMEM169 located at amino acids 160-180 and 211-231.[1] The N and C terminus are both located in the cytoplasmic domain.[11] The conceptual translation provides further annotation of Homo sapiens TMEM169 protein.

The specific structure of TMEM169 is unknown, although includes both alpha helices and beta sheets.[12]

The promoter (GXP_6745619) is 1242 base pairs at coordinates 216080866-216082107.[13] It supports 11 coding transcripts.

Schematic illustration of TMEM169 promoters (green) and exons (blue).

Table 2. There are four promoters that result from TMEM169 search on Genomatix.[13]

RNA sequencing data revealed TMEM169 is expressed ubiquitously, although it displays high expression in the brain, particularly during fetal development.[1] HPA RNA-seq normal tissues for TMEM169 were obtained from 95 human tissue samples. The HPA RNA-seq demonstrates highest expression of TMEM169 in the brain (RPKM=3.159). Particularly, in the fetal brain (RPKM= 1.583) and cerebellum(RPKM=0.795).[1]

GEO Profile: GDS3113/220527[14]

The highest expression of TMEM169 is found in the fetal brain. TMEM169 tends to have a high expression in the brain relative to other tissues, although not to other genes.

The use of polyclonal TMEM169 antibody (NBP2-69796) of a human melanoma cell line (SK-MEL-30) in the host of rabbit demonstrates TMEM169 localization to nucleoplasm, cytosol and centrosome.[15] Strong positivity in glial cells is revealed through immunohistochemical staining of the human cerebral cortex with antibody HPA074877.[16]

Conceptual Diagram of Homo sapiens TMEM169 highlighting domains and post-translational modifications

The MyHits[17] Tool revealed two types of conserved predicted post-translational modifications.

Orthologs are found in over 300 organisms within the kingdom metazoan.[1][8] There are not any orthologs found in fungi or plants. Invertebrates are the most distantly related orthologs, according to BLAST[3] searches. The subset of closely related organisms include mammals, reptiles, birds, and amphibians (E-value 1e-177 to 1e-124). These orthologs range from 78% to 93% sequence similarity to the human protein. Moderately related orthologs to human TMEM169 protein include fish and cephalochordates (similarity= 62%-75%; E-value= 3e-120 to 1e-71). Protein sequences of hemichordates, arthropods, and mollusks are the most distantly related to the human protein sequence (similarity= 56%-64%; E-value= 2e-58 to 1e-44).[3] The most distantly related organism with TMEM169 ortholog is Anopheles albimanus, within the taxonomic group Arthropoda. The size of the gene family for Anopheles albimanus is one and there is only one isoform.[20]

A portion of amino acid conservation of distant Homo sapiens TMEM169 orthologs is illustrated, highlighting transmembrane domains. The darker shade reflects higher conservation. The red boxes identify transmembrane domains.

Rate of Divergence of TMEM169

Table 1. Identified orthologs of Homo sapiens TMEM169 protein. The table is organized by increasing DOD (data of divergence from the human lineage) and then by sequence similarity to the human protein (%). The date of divergence was calculated using TimeTree.[21] Seq. is an abbreviation for sequence.

TMEM169 gene first appeared in invertebrates, more specifically in arthropods and mollusks. The approximate date of divergence from humans for arthropods and mollusks is 797 million years ago (MYA).[22] Based upon comparison of the evolution for cytochrome C (a quickly evolving protein) and fibrinogen alpha chain (a slowly evolving protein), TMEM169 gene is evolving at a moderate pace.