DEAF1

Official Full Name

DEAF1 transcription factor

Organism

Homo sapiens

GeneID

10522

Background

This gene encodes a zinc finger domain-containing protein that functions as a regulator of transcription. The encoded proteins binds to its own promoter as well as to that of several target genes. Activity of this protein is important in the regulation of embryonic development. Mutations in this gene have been found in individuals with autosomal dominant cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

Synonyms

SPN; NUDR; VSVS; MRD24; ZMYND5; NEDHELS;

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Detailed Information

Deformed epidermal autoregulatory factor-1 (DEAF1), encodes a zinc finger domain-containing protein that functions as an auto-regulator of transcription, essential for central nervous system and early embryonic development. It is comprised of multiple structural domains including a SAND domain, a monopartite nuclear localization signal (NLS) and a leucine-rich nuclear export signal (NES), and a cysteine-rich MYND domain. This gene encoded proteins binds to its own promoter with multiple copies of 5'-TTC[CG]G-3' (TTCG motifs) as well as to that of several target genes in regulatory regions, like HNRPA2B1 gene. It can also bind to the retinoic acid response element (RARE) 5'-AGGGTTCACCGAAAGTTCA-3'. Activity of this protein is significant in the regulation process of embryonic development. Disruption of Deaf1 function results in embryonic arrest and severe defects in early embryonic patterning in drosophila. DEAF1 activates the proenkephalin gene independently of promoter binding, probably through protein-protein interaction. When secreted, it behaves as an inhibitor of cell proliferation, by arresting cells in the G0 or G1 phase. DEAF1 has been described as a nuclear dimeric protein and suppressin as a secreted monomeric protein. Besides, DEAF1 is required in the process of neural tube closure and skeletal patterning. It also regulates epithelial cell proliferation and side-branching in the mammary gland, and controls the expression of peripheral tissue antigens in pancreatic lymph nodes.

Figure 1 DEAF1 detected in Nucleoplasm and Nucleoli fibrillar center

Deaf1 and Diseases

Diseases associated with DEAF1 include Dyskinesia, Seizures, And Intellectual Developmental Disorder and Mental Retardation, Autosomal Dominant 24. Defective DEAF1 could confer a growth advantage to the mutated cells influencing the development and progression of neoplasia, e.g. in the case of colorectal carcinomas. Subcellular location in colorectal carcinomas (cytoplasmic or nuclear) is a prognostic factor that identifies a subgroup of patients with reduced survival. In addition, changes in the subcellular location correlates with the proliferative status of the cells. Among its related pathways are Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways.

Intellectual disability is a common neurodevelopmental disorder with high clinical and genetic heterogeneity, that is frequently caused by de novo gene mutations. Mutations in this functional gene of DEAF1 have been found in individuals with autosomal dominant cognitive disability. Different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. Alternative splicing leads to multiple transcript variants. Recent studies using clinical exome sequencing (CES) have identified a potential role for DEAF1 in neurodevelopmental disorder. According to a series of functional assays, variants identified in Li Chen's study are likely to change DEAF1 protein conformation based on changes in amino acid charge, steric effect, hydrophobic or ionic interactions, and thus potentially damage protein function. Among the variants, missense variants located within the SAND and NLS domains have been identified, which are important regions for transcriptional activation or repression. The former region is essential for DNA binding (via its KDWK motif) and protein-protein interactions. These variants impair DEAF1 transcriptional activity, block DNA-binding, and alter subcellular localization, and as a consequence, likely contribute to the associated phenotypes in individuals with DEAF1-associated neurodevelopmental disorder. The serotonin-1A receptor(5-HT1A) is the primary somatodendritic autoreceptor that inhibits the activity of serotonergic raphe neurons, which is implicated in mood disorders, like depression, suicide, and panic disorder. It is also expressed in nonserotonergic cortical and limbic neurons. Deaf-1 and Hes5 has been identified as two transcription factors with cell-specific activity. The enhancer activity of Deaf-1 was orientation independent and competed out Hes5 repression at the C(-1019) site of 5-HT1A, which has functional promoter polymorphism. According to Margaret Czesak's excellent research, the intrinsic activity of Deaf-1 at the 5-HT1A promoter is opposite in presynaptic versus postsynaptic neuronal cells and requires deacetylation. Cell-specific regulation by Deaf-1 could underlie region-specific alterations in 5-HT1A receptor expression in different mood disorders.

References:

Nabais Sá MJ, et al. De novo and biallelic DEAF1 variants cause a phenotypic spectrum. Genet Med. 21(9):2059-2069.
Maulik PK, Mascarenhas MN, Mathers CD, Dua T, Saxena S. Prevalence of intellectual disability: a meta-analysis of population-based studies. Res Dev Disabil. 2011;32(2):419–426.
Veraksa A, Kennison J, McGinnis W. DEAF-1 function is essential for the early embryonic development of Drosophila. Genesis. 2002;33(2):67–76.
Li Chen, et al. Functional analysis of novel DEAF1 variants identified through clinical exome sequencing expands DEAF1-associated neurodevelopmental disorder (DAND) phenotype. Hum Mutat. 2017; 38(12):1774-1785.
M.J. Bottomley, M.W. Collard, J.I. Huggenvik, Z. Liu, T.J. Gibson, M. Sattler. The SAND domain structure defines a novel DNA-binding fold in transcriptional regulation. Nat. Struct. Biol., 8 (2001), pp. 626-633.
Margaret Czesak, et al. Cell-Specific Repressor or Enhancer Activities of Deaf-1 at a Serotonin 1A Receptor Gene Polymorphism. J. Neurosci. 2006. 26(6):1864 –1871.

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