De novo missense variants in the DEAF1 gene that resulted in impaired transcriptional regulation of the DEAF1 promoter were identified in four individuals from three reports (PMIDs 21076407, 23020937, 24726472). All four individuals presented with intellectual disability, mild motor delay, and severely affected speech development; three of these individuals also displayed severe behavioral problems consisting of autism/autistic behavior, hyperactive behavior, compulsive behavior, and aggressive behavior with striking mood swings and poor eye contact. Chen et al., 2017 identified potentially deleterious heterozygous DEAF1 variants in six novel individuals presenting with intellectual disability, motor delay, and autistic behavior. Rare de novo heterozygous missense variants that were predicted to be damaging have been observed in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014), as well as in ASD probands from the Autism Simplex Collection (TASC) and the Autism Clinical and Genetic Resources in China (ACGC) cohorts (Geisheker et al., 2017). Biallelic variants in the DEAF1 gene have also been observed in individuals presenting with an autosomal recessive neurodevelopmental disorder (dyskinesia, seizures, and intellectual developmental disorder; OMIM 617171); autistic features have been observed in a subset of these individuals (Rajab et al., 2015; Gund et al., 2016; Trujillano et al., 2017; Chen et al., 2017). Phentoypic characterization of a previously unreported cohort of 17 individuals with de novo DEAF1 variants and 5 individuals with biallelic DEAF1 variants in Nabais Sa et al., 2019 found that autism was present in 16 individuals with a de novo DEAF1 variant, as opposed to 1 individual with a biallelic DEAF1 variant. Furthermore, many of the de novo DEAF1 variants reported by Nabais Sa et al., 2019 were experimentally shown to impair transcriptional regulation of the DEAF1 promoter. Three additional de novo missense variants in the DEAF1 gene were identified in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified DEAF1 as a candidate gene with a false discovery rate (FDR) 0.01. A de novo loss-of-function variant and three rare and potentially damaging missense variants in the DEAF1 gene were reported in ASD probands from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified DEAF1 as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
Transcription factor that binds to sequence with multiple copies of 5'-TTC[CG]G-3' present in its own promoter and that of the HNRPA2B1 gene and down-regulates transcription of these genes. Binds to the retinoic acid response element (RARE) 5'-AGGGTTCACCGAAAGTTCA-3'. Activates the proenkephalin gene independently of promoter binding, probably through protein-protein interaction. When secreted, behaves as an inhibitor of cell proliferation, by arresting cells in the G0 or G1 phase. Required for neural tube closure and skeletal patterning.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems.
Deaf1 knockout in mice increases 5-HT1A autoreceptor expression with no change in the corresponding serotonin1A autoreceptor mediated current in serotonin neurons, 5-HT1A autoreceptor antagonist, DPAT-induced hypothermia increased in male but not female Deaf1 homozygous knockout mice, and reduced with succeeding generations, Deaf1 homozygous knockout mouse models also showed mild anxiety in a sex and test dependent manner, No depression was observed in either sexes of Deaf1 homozygous knockout mouse models.
References
Type
Title
Author, Year
Additional
Defective neural tube closure and anteroposterior patterning in mice lacking the LIM protein LMO4 or its interacting partner Deaf-1.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Deaf1 gene is mutated by disrupting exons 2 and 3 that encode the SAND domain and replacing amino acids 192-269 with a PGK-neo cassette. Deaf-1 chimeras were crossed with Gata1-cre transgenic mice to generate progeny that were heterozygous, which wer further bred to give homozygous knockouts. Gata1-Cre is expressed early in embryogenesis.
Allele Type: Targeted (conditional knockout)
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Unreported
Mutant ES Cell Line: CJ-7 ES cells
Model Source: Unreported
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Deaf1 gene is mutated by disrupting exons 2 and 3 that encode the SAND domain and replacing amino acids 192-269 with a PGK-neo cassette. Deaf-1 chimeras were crossed with Gata1-cre transgenic mice to generate progeny that were heterozygous. Gata1-Cre is expressed early in embryogenesis.
Allele Type: Targeted (conditional knockout)
Strain of Origin: C57BL/6
Genetic Background: C57BL/6
ES Cell Line: Unreported
Mutant ES Cell Line: CJ-7 ES cells
Model Source: Unreported
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice with a targeted homozygous disruption of exons 25 of both alleles of Deaf1 were produced and backcrossed onto a C57BL/6 background for seven generations.
Allele Type: Targeted(knockout)
Strain of Origin: Unreported
Genetic Background: C57BL/6
ES Cell Line: Unreported
Mutant ES Cell Line: Unreported
Model Source: Unreported
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Mice with a targeted heterozygous disruption of exons 25 of Deaf1 were produced and backcrossed onto a C57BL/6 background for seven generations.
Allele Type: Targeted(knockout)
Strain of Origin: Unreported
Genetic Background: C57BL/6
ES Cell Line: Unreported
Mutant ES Cell Line: Unreported
Model Source: Unreported
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 2-5 of Deaf1 using Nestin-cre, in neuronal, glial and other cell types in the central and peripheral nervous system
Allele Type: Conditional loss-of-function
Strain of Origin: Unreported
Genetic Background: C57BL/6
ES Cell Line: Unreported
Mutant ES Cell Line: Unreported
Model Source: Unreported
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of exons 2-5 of Deaf1 using Nestin-cre, in neuronal, glial and other cell types in the central and peripheral nervous system
Allele Type: Conditional loss-of-function
Strain of Origin: Unreported
Genetic Background: C57BL/6
ES Cell Line: Unreported
Mutant ES Cell Line: Unreported
Model Source: Unreported
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice with a targeted homozygous disruption of exons 25 of both alleles of Deaf1 were produced and backcrossed onto a BALB/c background for seven generations.
Allele Type: Targeted(knockout)
Strain of Origin: Unreported
Genetic Background: BALB/c
ES Cell Line: Unreported
Mutant ES Cell Line: Unreported
Model Source: Unreported
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
First, third and later generation mice harboring homozygous null deletion of Deaf1 on a mixed background.
Allele Type: Targeted(knockout)
Strain of Origin: C57BL6
Genetic Background: C57Bl/6*BALB/c
ES Cell Line: Unreported
Mutant ES Cell Line: Unreported
Model Source: Charles River Laboratories, Montreal, Canada
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
First generation mice harboring heterozygous null deletion of Deaf1 on a mixed background.
Allele Type: Targeted
Strain of Origin: C57BL6
Genetic Background: C57Bl/6*BALB/c
ES Cell Line: Unreported
Mutant ES Cell Line: Unreported
Model Source: Charles River Laboratories, Montreal, Canada
Description: Deaf1 conditional homozygous knockout mice showed increased frequency of exencephaly (cranial neural tube closure) than wildtype mice
Exp Paradigm: Presence of open cranial neural tube recorded
Description: Deaf1 homozygous conditional knockout mice showed abnormalities in the rib cage, cervical vertebrae, attachment of the 8th rib to the sternum, bifurcated or fused ribs, fusion of the first and second ribs, aberrant attachment of anterior tubercules to cervical vertebrae and mis-attachment of the anterior tubercule to c7 instead of c6, compared to controls
Exp Paradigm: Alcian blue or alizarin red staining
Description: Deaf1 homozygous conditional knockout mice without exencephaly (cranial neural tube closure) survived to the same frequency as wildtype mice, as expected by mendelian ratios. exencephalic mice died shortly after birth.
Exp Paradigm: Males and females
Description: Deaf1 conditional homozygous knockout mice showed no deaf1 protein compared to controls
Exp Paradigm: 30g total protein lysate was used for western
Description: Deaf1 conditional heterozygous knockout mice showed increased frequency of exencephaly (increased cranial neural tube closure) than wildtype mice
Exp Paradigm: Presence of open cranial neural tube recorded
Description: Deaf1 heterozygous conditional knockout mice showed bifurcation and fusion of the eighth and ninth ribs, fusion of the first and second ribs, aberrant attachment of anterior tubercules to cervical vertebrae, mis-attachment of the anterior tubercule to c5 and aberrant attachment of the first rib to c7 instead of t1, compared to control
Exp Paradigm: Alcian blue or alizarin red staining
Description: Deaf1 conditional heterozygous knockout mice showed reduced deaf1 protein compared to controls
Exp Paradigm: 30g total protein lysate was used for western
Description: Deaf1 conditional homozygous knockout mice showed enhanced ability at finding a submerged platform moved to the opposite quadrant than control mice at 48 hours after training with a visible platform. on subsequent trials learning curves were similar to controls.
Exp Paradigm: Males only
Description: Deaf1 conditional heterozygous knockout mice showed 11 to 49 fold reductions of deaf1 mrna transcript in various regions of the brain (frontal cortex, hippocampus, midbrain, temporal cortex, cerebellum) compared to controls
Exp Paradigm: Males only
Description: Deaf1 homozygous null mice of the third generation and later show increased serotonin 1a autoreceptor levels compared to controls
Exp Paradigm: Males and females
Description: Deaf1 homozygous null male and female mice of the third generation and later show 5-ht1a receptor-mediated outward currents of similar magnitude in recordings from raphe 5-ht neurons as in wild-type mice, however examining the dataset for sex-specific alterations in the responsiveness of 5-ht1a receptors show a 60% reduction in male deaf1 ko mice only, indicating functional activity of 5-ht1a autoreceptors present in deaf1 homozygous null mice declines over generations, despite increased abundance of 5-ht1a autoreceptors, no difference was observed in deaf1 ko females
Exp Paradigm: Effects of bath administration of the 5-ht1a agonist 5-ct (100 nm) was monitored, males and females
Description: Deaf1 homozygous null mice show increased dpat (5- ht1a agonist) induced hypothermia compared to controls
Exp Paradigm: Hypothermia induced by acute administration of the 5- ht1a agonist dpat (0.5 and 0.25 mg/kg) was measured as an index of 5-ht1a autoreceptor responsiveness in vivo in males and females
Description: In open field test, male deaf1 ko mice avoid the centre, in the light-dark test, male deaf1 ko mice showed reduced time in the light and increased latency to enter the dark chamber, consistent with an anxiety phenotype, overall two of three tests show male deaf1 ko mice have increased anxiety compared to wildtype controls, in the elevated plus maze female deaf1 mice showed a 75% increased reduction in time spent in open arms compared to wildtype mice,
Exp Paradigm: Open and closed arm time was monitored by overhead camera-open field test
Description: In open field test, male deaf1 ko mice avoid the centre, in the light-dark test, male deaf1 ko mice showed reduced time in the light and increased latency to enter the dark chamber, consistent with an anxiety phenotype, overall two of three tests show male deaf1 ko mice have increased anxiety compared to wildtype controls, in the elevated plus maze female deaf1 mice showed a 75% increased reduction in time spent in open arms compared to wildtype mice,
Exp Paradigm: Open and closed arm time was monitored by overhead camera- light-dark exploration test
Description: In the light-dark test the female deaf1 knockouts spent more time in the light compared to wildtypes suggesting reduced anxiety
Exp Paradigm: Movement within the compartments was detected using infrared transmitters
