The GRHL2 located on chromosome 8q22.3 is on the forward strand and spans 177287 bp on the genome. It has 16 exons. The primary mRNA transcript 1 (NM_024915.3) is 5231 bp in length and contains an open reading frame of 1878 bp (NCBI ,2017).

The human GRHL2 gene is located on chromosome 8 and contains 16 exons.

It appears that an internal 5 splicing site within the first exon of GRHL2 generates an alternate GRHL2 mRNA (NM_001330593) with a 203-base deletion containing the first Met encoding AUG codon in its 5-end. This results in the utilization of the second AUG within exon 2 giving rise to an amino-terminally truncated (16 residues) GRHL2 isoform (NP_001317522.1), GRHL2v (17-625) that displays a disrupted transactivation function.

GRHL2 variant 1 transcript encodes a 625 amino acids (aa) long protein (NP_079191.2). Based on GHRL2 and its Drosophila homolog GRH, the protein isoform 1 contains transcription activation domain at the amino-terminus (1-93 aa) and a large CP2 Transcription Factor domain between 119-438 aa that is responsible for DNA binding as well as a dimerization domain at the carboxyl-terminus (Attardi and Tijan, 1993, Kokoszynska et al., 2017; Uv, Thompson and Bray, 1994). Resulting from the alternative splicing of GHRL2 transcript, GRHL2 isoform 2 lacks the first 16 amino-acids and is a 609 aa long protein (NP_001317522.1). GRHL2 isoform is reported to counteract the oncogenic potential of GRHL2 isoform 1 by acting as a dominant negative manner (Werner et al., 2013).
Proteomic analyses also suggest that GRHL2 is a phosphoprotein in various normal and cancerous tissues as well as in cell lines (Mertins et al., 2016).

GRHL2 protein is a transcription regulator that has a conserved CP2 domain.

In human adults, GRHL2 is expressed in the placenta, brain, kidney, prostate, thymus, lung, salivary gland, mammary gland, digestive tract, and pancreas (Wilanowski et al., 2002; Peters et al., 2002).
It is also reported that MIR194 and MIR217 inhibit the cellular proliferation and promote cellular differentiation by targeting the GRHL2 translation (Yu et al., 2017; Zhu et al.,2016).

GRHL2 is localized primarily in the nucleus (Chen et al., 2010; Petrof et al., 2014). GRHL2 is also observed to be localized in the cytoplasm and at the inner cell membrane (Petrof et al., 2014).

GRHL2 is a transcription factor. The GRHL2 encodes a 71 kDa protein functions as DNA binding protein that interacts with permutations of the consensus sequence 5-AACCGGTT-3 (Werner et al., 2013). GRHL2 appears to act as transcription repressor and/or activator depending on chromatin context of target genes (Mehrazarin.et al., 2015).
Observations with experimental animal models indicate that the knock-out of, or nonsense mutations in, the mouse Grhl2 gene results in embryonic lethality due to defects in neural tube closure, epithelial morphogenesis, and barrier formation by de-regulation of cell junction protein expressions (Werth et al.,2010; Pyrgaki, Liu and Niswander, 2011). This finding emphasizes the essentiality of Grhl2 for epithelial and neural morphogenesis during embryogenesis.
GRHL2 is also implicated in the carcinogenesis of various tissues and organs. Consistent with its role in epithelial morphogenesis, GRHL2 is shown act as tumor-suppressor by controlling the epithelial-mesenchymal transition (EMT), an essential characteristic of tumor progression (Wellner et al., 2009). In contrast, GRHL2 is also reported to act as an oncogene by promoting cell proliferation and survival (Cieply et al., 2013). Although underlying reasons are yet unclear, de-regulation of tissue/organ specific expression of the GHRL2 gene together with tissue/organ specific gene targets of GHRL2 is suggested to underlie the dual effects of GRHL2 on carcinogenesis (Wellner et al., 2009).

GRHL2 is a conserved gene among vertebrates and in Drosophila.

Tyr to His substitution at the position 398 and Ile to Lys at 498 of GHRL2 are observed in ectodermal dysplasia (Petrof et al., 2014). In addition, single nucleotide insertion at the position 1609 is reported to lead to frame shift and early stop codon in the encoding transcript (Peters et al., 2002).

Haploinsufficiency for GRHL2 implicated in non-syndromic sensorineural deafness- autosomal dominant type 28 (DFNA28), due to frameshift mutations and single nucleotide polymorphism in the gene (Van Laer et al., 2007), are associated with hearing loss. (Peters et al., 2002). These variations in the GRHL2 gene are suggested to likely result in deregulated gene expressions encoding for cell junction proteins and ion channels in the otic epithelial cells, which are important for the inner ear development and homeostasis (Han et al., 2011).
It is also reported that mutations in the GRHL2 sequences encoding DNA binding domain result in an autosomal-recessive ectodermal Dysplasia syndrome (Petrof et al., 2014).