Covered on Genetics Home Reference: nonsyndromic hearing lossFrom NCBI Gene: Deafness, autosomal dominant 28Ectodermal dysplasia/short stature syndromeFrom UniProt: Ectodermal dysplasia/short stature syndrome (ECTDS): An autosomal recessive ectodermal dysplasia syndrome characterized by nail dystrophy and/or loss, oral mucosa and/or tongue pigmentation, abnormal dentition, keratoderma affecting the margins of the palms and soles, focal hyperkeratosis of the dorsal aspects of the hands and feet, and short stature. [MIM:616029] Deafness, autosomal dominant, 28 (DFNA28): A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA28 is characterized by mild to moderate hearing loss across most frequencies that progresses to severe loss in the higher frequencies by the fifth decade. [MIM:608641]

     From NCBI Gene: The protein encoded by this gene is a transcription factor that can act as a homodimer or as a heterodimer with either GRHL1 or GRHL3. Defects in this gene are a cause of non-syndromic sensorineural deafness autosomal dominant type 28 (DFNA28).[provided by RefSeq, Mar 2009] From UniProt: Transcription factor playing an important role in primary neurulation and in epithelial development (PubMed:25152456). Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' acting as an activator and repressor on distinct target genes (By similarity). During embryogenesis, plays unique and cooperative roles with GRHL3 in establishing distinct zones of primary neurulation. Essential for closure 3 (rostral end of the forebrain), functions cooperatively with GRHL3 in closure 2 (forebrain/midbrain boundary) and posterior neuropore closure (By similarity). Regulates epithelial morphogenesis acting as a target gene-associated transcriptional activator of apical junctional complex components. Up-regulates of CLDN3 and CLDN4, as well as of RAB25, which increases the CLDN4 protein and its localization at tight junctions (By similarity). Comprises an essential component of the transcriptional machinery that establishes appropriate expression levels of CLDN4 and CDH1 in different types of epithelia. Exhibits functional redundancy with GRHL3 in epidermal morphogenetic events and epidermal wound repair (By similarity). In lung, forms a regulatory loop with NKX2-1 that coordinates lung epithelial cell morphogenesis and differentiation (By similarity). In keratinocytes, plays a role in telomerase activation during cellular proliferation, regulates TERT expression by binding to TERT promoter region and inhibiting DNA methylation at the 5'-CpG island, possibly by interfering with DNMT1 enzyme activity (PubMed:19015635, PubMed:20938050). In addition, impairs keratinocyte differentiation and epidermal function by inhibiting the expression of genes clustered at the epidermal differentiation complex (EDC) as well as GRHL1 and GRHL3 through epigenetic mechanisms (PubMed:23254293).

The following transcription factors affect gene expression:

• GR
• GR-alpha
• GR-beta
• C/EBPbeta
• AREB6

Tissue specificity:

Expressed in keratinocytes (at protein level). Highly expressed in placenta, prostate, brain and kidney. Lower-level expression in a variety of epithelial tissues such as thymus, lung, salivary gland, mammary gland and digestive tract. Expressed in the cochlear.

Induction:

Expressed in proliferating cells, the expression decreases during senescence. In keratinocytes, expression levels decrease upon calcium exposure.

Molecular Function:

• Chromatin Dna Binding
• Intronic Transcription Regulatory Region Sequence-Specific Dna Binding
• Sequence-Specific Dna Binding
• Transcriptional Activator Activity, Rna Polymerase Ii Transcription Regulatory Region Sequence-Specific Binding
• Transcription Factor Activity, Sequence-Specific Dna Binding

Biological Processes:

• Bicellular Tight Junction Assembly
• Brain Development
• Camera-Type Eye Development
• Cardiac Ventricle Morphogenesis
• Cell Adhesion
• Cell Junction Assembly
• Cell Proliferation
• Embryonic Cranial Skeleton Morphogenesis
• Embryonic Digit Morphogenesis
• Epidermis Development
• Epithelial Cell Morphogenesis
• Epithelial Cell Morphogenesis Involved In Placental Branching
• Epithelium Migration
• Face Development
• Lung Epithelial Cell Differentiation
• Lung Lobe Morphogenesis
• Multicellular Organism Growth
• Negative Regulation Of Keratinocyte Differentiation
• Neural Tube Closure
• Neural Tube Development
• Positive Regulation Of Telomerase Activity
• Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
• Regulation Of Dna Methylation