The human KIAA1199 transcript spans 7080 base pairs on chromosome 15 in the region 15q25.1. It contains 29 exons, 28 of which are coding, and 28 introns. The transcriptional start site is within the second exon. There is a canonical TATA-box present in the KIAA1199 promoter region at -31 to -27 base pairs, as well as a GC-box at -248 to -243 base pairs. However, this GC-box was not found to be required for transcriptional activation of KIAA1199, nor was there any methylation of the cytosines found within this region, which is often an important feature of GC-boxes. KIAA1199 also contains a CpG island within the first intron (+525 50 +1025). The methylation status of this CpG island was found to effect the expression level of KIAA1199, with high levels of DNA methylation found in non-aggressive, low expressing, cancer cell lines (Kuscu et al., 2012).

An AP-1 binding site, located between -48 and -45 within the KIAA1199 promoter, was found to be important for KIAA1199 promoter activity. AP-1 was found to directly bind to this region in order to activate transcription of KIAA1199. AP-1 transcription factors have been associated with increased promoter activity of genes associated with cancer. Additionally, among four potential NF-κB binding sites, the site furthest from the transcriptional start site (-1345 to -1333) was found to play a role in KIAA1199 promoter activation. NF-κB was found to directly bind to this site to increase transcription of KIAA1199 (Kuscu et al., 2012).

The KIAA1199 open reading frame consists of 4083 base pairs, which encodes a protein 1361 amino acids in length. It has a predicted molecular weight of approximately 163 kDa. The KIAA1199 protein has a G8 domain between a.a. 44-166, which is a novel domain that contains eight conserved glycines and consists of five β-strand pairs (He et al., 2006). Several disease related proteins contain this domain, including polyductin protein (PKHD1) and transmembrane protein 2 (TMEM2), although the exact function of the G8 motif remains unclear (He et al., 2006). A GG domain, characterized by seven β-strands and two α-helices, can also be found within the KIAA1199 protein (Guo et al., 2006). This novel domain also has no known function. KIAA1199 is also predicted to have a cleavable signal peptide at its NH2-terminus (Sabates-Bellver et al., 2007). KIAA1199 has been demonstrated to be N-linked glycosylated (Tiwari et al., 2013).

Northern blot analysis of normal human tissues revealed expression of KIAA1199 mRNA in various tissues, with the highest levels found in the brain, placenta, lung, and testis (Michishita et al., 2006). KIAA1199 is also expressed in various cell types found in the inner ear (Abe et al., 2003; Usami et al., 2008), and in dermal fibroblasts of the skin (Yoshida et al., 2013). Increased levels of KIAA1199 have also been demonstrated in numerous cancer tissues compared to normal tissues, including colorectal adenomas (Sabates-Bellver et al., 2007).

Cytoplasmic and nuclear staining for KIAA1199 has been observed in gastric and colon cancer tissue samples (Sabates-Bellver et al., 2007; Matsuzaki et al., 2009; Birkenkamp-Demtroder et al., 2011). More detailed subcellular localization revealed expression of exogenous and endogenous KIAA1199 within the endoplasmic reticulum (ER) of various cell types (Evensen et al., 2013; Tiwari et al., 2013). KIAA1199 was found to interact with the ER chaperone binding immunoglobulin protein (BiP)/glucose-regulated protein (GRP-78), which further supports the ER localization of KIAA1199 (Evensen et al., 2013). Secretion of KIAA1199 has also been demonstrated for certain cell types (Tiwari et al., 2013).

KIAA1199 plays a key role in cancer progression via increasing cancer cell migration and invasion, which are necessary steps for cancer metastasis. Expression of KIAA1199 in non-aggressive cancer cell lines leads to an epithelial-to-mesenchymal transition along with increased migratory capabilites. Furthermore, knockdown of KIAA1199 leads to a loss of mesenchymal characteristics with decreased invasive and migratory abilities, as well as reduced metastastic potential (Evensen et al., 2013).
A role for KIAA1199 in maintaining ion homeostasis, and more specifically calcium signaling, has also been suggested (Abe et al., 2003; Tiwari et al., 2013). KIAA1199-mediated migration was found to involve elevated cytosolic calcium levels followed by protein kinase C alpha (PKCα) translocation/activation. This change in cytosolic calcium is due to increased release of calcium from the ER via an unknown mechanism induced by KIAA1199 (Evensen et al., 2013). Additional studies revealed an interaction with KIAA1199 and inositol 1,4,5-triphosphate receptor 3 (ITPR3) which is a ligand-gated ion channel located on the ER membrane that is known to mediate the release of calcium from the ER (Tiwari et al., 2013).
KIAA1199 is thought to be a target of the Wnt signaling pathway and a potential player in the progression of colorectal adenomatous (Sabates-Bellver et al., 2007; Tiwari et al., 2013). Additionally, silencing of KIAA1199 was shown to alter the expression of genes known to be involved in the Wnt/β-catenin pathway and decrease cell proliferation (Birkenkamp-Demtroder et al., 2011).
In human skin fibroblasts, KIAA1199 expression was found to cause increased degradation of hyaluronan (HA), which is a glycosaminoglycan found in the extracellular matrix surrounding tissues. It acts as a structural component and can affect cell signaling and cellular behavior, including angiogenesis and cell migration (Yoshida et al., 2013).

The KIAA1199 gene product shares 38% identity (63% similarity) with transmembrane protein 2 (TMEM2). A small region within the KIAA1199 gene product (aa 55-155) also shares 38% identity (57% similarity) with polyductin protein (PKHD1) (Abe et al., 2003). However, none of these homologies revealed any functional information.

Nine DNA variants of the KIAA1199 gene were identified, six of which were missense (R187C, R187H, H783R, H783Y, V1109I, and P1169A) and three of which were synonymous substitutions (L532L, P619P, D800D). R187C, R187H, H783Y, and V1109I were found only in families with nonsyndromic hearing loss, suggesting a potential role for these specific mutations in this disease state (Abe et al., 2003).