Recurrent mutations in the ADNP gene have been identified in multiple individuals with ASD as described below. Two de novo frameshift variants in ADNP were identified in unrelated simplex ASD cases in two reports by O'Roak and colleagues in 2012 (PMIDs 22495309 and 23160955). An additional seven de novo LoF variants were identified in patients with ASD in Helsmoortel et al., 2014, giving a current total of nine de novo LoF variants in ADNP gene in ASD cases; the probability of detecting eight or more de novo truncating events in ADNP was given as P=2.65 x 10-18 in this report (PMID 24531329). Furthermore, the frequency of shared clinical characteristics in ASD cases with LoF variants in ADNP (intellectual disability, facial dysmorphisms) led Helsmoortel and colleagues to conclude that ADNP mutations resulted in an autism syndrome. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified ADNP as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). 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 Zhou et al., 2022 identified ADNP as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
Potential transcription factor that may mediate some of the neuroprotective peptide VIP-associated effects involving normal growth and cancer proliferation. In brain, expression is stronger in the cerebellum and cortex regions.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
The ADNP homozygous knock out causes embryonic lethality. The heterozygous mice have normal, slightly delayed development and show reduced neuronal survival and some changes in gene expression (e.g., some transcription factors like Pax6).
References
Type
Title
Author, Year
Additional
Activity-dependent neuroprotective protein: a novel gene essential for brain formation.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Exons 3,4 and 5 of the Adnp gene were replaced with a neomycin cassette and a thymidine kinase gene, using homologous recombination. Following germline transmission the hetereozygous knockouts were crossed to generate homozygous mice.
Allele Type: Targeted (knockout)
Strain of Origin: 129/Sv
Genetic Background: 129/Sv*C57BL/6
ES Cell Line: 129/Sv
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The knock out model was generated by replacing exons 3,4 and 5 with a neomycin cassette and adding a thymidine kinase gene at the negative selection marker.
Allele Type: Targeted (knockout)
Strain of Origin: 129/Sv
Genetic Background: 129/Sv*C57BL/6
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Adnp het knock out mice were maintained in the ICR outbred background to circumvent breding problems. This resulted in more aggressive mice than the inbred background (the authors have noted).
Allele Type: Targeted (knockout)
Strain of Origin: 129/Sv
Genetic Background: 129/Sv*C57BL/6*ICR
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Multifactorial
Model Genotype:
Heterozygous
Mutation:
Adnp heterozygous knockout mice with exons 3, 4 and 5 of the adnp gene replaced with a neomycin cassette and a thymidine kinase gene, are exposed to a stress challenge through 48 hours of solitude in clean cage under constant bright illumination of about 500 lux.
Allele Type: Knockout
Strain of Origin: Not specified
Genetic Background: C57BL*129/Sv*ICR
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
ADNP exons 3, 4, and 5 were replaced with a neomycin selection cassette inserted by homologous recombination. The mouse model is identical to the construct of model M_ADNP_2_KO_HT but on a different background.
Allele Type: Targeted (knockout)
Strain of Origin: NA
Genetic Background: ICR
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: PMID 30106381 (Hacohen-Kleiman et al. 2018)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Try model carries the nm_001310086 (adnp_v001) c.2154t>a, p.tyr718* mutation; animals express a truncated adnp protein that lacks the nuclear localization signal
Allele Type: Knockout
Strain of Origin: Genetic Background: C57BL/6NJ
ES Cell Line: C57BL/6N
Mutant ES Cell Line: Model Source: Karmon et al., 2021
Description: Abnormally increased expression of oct4 (pou5f1) , a gene essential in maintenance of stem cells, at e8-8.5 unlike wt controls where this gene is downregulated at this stage, whereas the expression of pax6 was ablated in the anterior neural plate of the null embryos, unlike in wt embryos
Exp Paradigm: NA
Description: Adnp het mice have longer latencies in finding the visible platform than their wt, even though they do learn to find it in 60 s
Exp Paradigm: NA
Description: For this phenotype only the astrocyte form and structure were considered to count abnormal looking astrocytes (thorn shaped, swollen) was higher in 10-11 month old adnp het mice compared to age matched controls
Exp Paradigm: NA
Description: Retrograde axonal transport in the lateral part of olfactory nerve and glomerular layer is reduced in adnp mice, assessed by the signal intensity in memri
Exp Paradigm: Males and females
Manganese-enhanced magnetic resonance imaging (memri)
Description: Adnp het male and female mice show no preference towards novel unfamiliar mouse over familiar mouse, unlike controls
Exp Paradigm: Males and females
Description: Adnp het male mice show reduced preference for an unfamiliar 18 month old female mouse, once they have interacted with another female mouse over 6 trials (separated by 30 min) on the same day.
Exp Paradigm: NA
Description: Adnp het male mice show reduce social memory as they have long imes of ineractions, sniffing etc, with a female mouse over 6 trials whereas wt male mice reduce the time of interaction over that period
Exp Paradigm: NA
Description: Adnp het mice take longer to find the hidden platform on the first trial in the hidden platform test of morris water maze, testing reference memory ( stated by the authors).
Exp Paradigm: A pair of trials are conducted everyday for 5 days. the platform and start position of the mouse are kept constant on the same day over the paired trials, but changed every day. at first, the mouse was placed for 0.5 min on the platform and then placed in the water and the latency to reach the platform was measured (first test). this was repeated once the mouse found the platform ( it was allowed to remain on the platform for 0.5 min again before being placed in the water).
Description: Adnp het mice show reduced short term working memory in the second test trials conducted, showing increased latency to find the hidden platform again (see exp paradigm details) and they also do not learn the task by the 3rd day of testing, unlike wt controls
Exp Paradigm: A pair of trials are conducted everyday for 5 days. the platform and start position of the mouse are kept constant on the same day over the paired trials, but changed every day. at first, the mouse was placed for 0.5 min on the platform and then placed in the water and the latency to reach the platform was measured (first test). this was repeated (second test) once the mouse found the platform ( it was allowed to remain on the platform for 0.5 min again before being placed in the water).
Description: Number of cells expressing slc6a4 in the hippocampal ca1 is significantly increased in male adnp het mice only, compared to male adnp controls
Exp Paradigm: Males only
Description: There was a significant increase in the active form of gsk3/, phosphorylated at tyr279/216 at 9 months of age. at 2 months the active form was increased but did not reach significance.
Exp Paradigm: NA
Description: Number of cells expressing beclin1 (becn1) in the hippocampus is significantly reduced in female adnp het mice only, compared to female adnp controls
Exp Paradigm: Females only
Description: There was a 42% decrease in adnp mrna in the adnp het mice brain cortex, 38% reduction in the cerebellum and 50% reduction in the hippocampus
Exp Paradigm: Western blot: adnp protein
Description: Number of cells expressing voltage dependent calcium channel (vdcc), cacnb1 in the hippocampus is significantly reduced in male adnp het mice only, compared to male adnp controls
Exp Paradigm: Males only
Description: There was a 42% decrease in adnp mrna in the adnp het mice brain cortex, 38% reduction in the cerebellum and 50% reduction in the hippocampus
Exp Paradigm: Quantitative pcr (qrt-pcr)
Description: Number of cells expressing vdcc, cacnb1, in the hippocampus is significantly increased in female adnp het mice only, compared to female adnp controls
Exp Paradigm: Females only
Description: Adnp het male mice show significant decrease in stand time and step cycle compared with controls. adnp het male and female mice show decrease in stride length compared with controls. gait was more severely affected in male than in female mutants indicating sexual dimorphism.
Exp Paradigm: NA
Description: Adnp het male but not female mice show decrease in latency to fall off and inverted wire cage lid compared with controls, indicating sexual dimorphism.
Exp Paradigm: NA
Description: Adnp het male but not female mice show increase in hippocampal and cortical shaft synapse density exhibiting sexual dimorphsm.
Exp Paradigm: NA
Dti: fractional anisotropy or relative anisotropy in brain regions3
Decreased
Description: Male mutants show decrease in fractional anisotropy in the hippocampus compared with controls, indicating structural impairment in the hippocampus.
Exp Paradigm: Hippocampus
Description: Adnp het mutants males ut not females show increased localization of psd95 (marking immature synapses) in the dendritic shafts rather than spines compared with mutants, exhibiting sexual dimorphism.
Exp Paradigm: NA
Description: Adnp het male and female mice show decreased dendritic spine density compared with controls, with a more severe reduction in the cortex than the hippocampus in males.
Exp Paradigm: Crossing with a membrane gfp reporter mouse line allows for assays on dendritic spine density. adnp het females were crossed with l15 male mice (on a c57bl/6 background), to produce adnp het mice with neuronal gfp expression.
Description: Male mutants show increase in mean diffusivity compared with controls, indicating structural impairment in the hippocampus.
Exp Paradigm: Hippocampus
Description: Male mutants show a decrease in total sniffing time compared with male controls indicating a change in olfaction either due to a change in the sensory perception in the olfactory epithelium or due to unknown factors not tested here.
Exp Paradigm: NA
Description: Female mutants show increase in total sniffing time in the olfactory discrimination test compared with female controls indicating a change in olfaction either due to a change in the sensory perception in the olfactory epithelium or due to unknown factors not tested here.
Exp Paradigm: NA
Description: Adnp het female but not male mice show decreased odor discrimination compared with controls indicating sexual dimorphism.
Exp Paradigm: NA
Description: Both male and female adnp het mice show significantly reduced social memory and spend less time with novel stimulus mouse, compared to familiar mouse in the three chamber test
Exp Paradigm: NA
Description: Adnp het female but not male mice prefered the inanimate object (empty cup) over the mouse stimulus compared to controls, indicating sexual dimorphism.
Exp Paradigm: NA
Description: Adnp het pups show an earlier appearance of the development of ear twitching, no change in the time of development of air righting reflex, and a delay in appearance of negative geotaxis compared with controls.
Exp Paradigm: Daily measurements for length, weight and eyeopeningobservation, until p21.
Description: Adnp het male mice showed lower body lengths between p13 and p21 but not before p13, compared with controls. adnp het female mice show lower body lengths compared with controls between p15 and p21 but not before p15 compared with controls.
Exp Paradigm: NA
Description: Adnp het male and female mice show decrease in body weight gain between p18 and p21 in males and between p13 and p21 in females compared with controls.
Exp Paradigm: NA
Description: Male mutants show decrease in time spent exploring the novel object compared with controls.
Exp Paradigm: Fraction of time spent with the novel object in relation to the total time spent sniffing both novel and familiar objects is measured (d2 score)
Description: Mutants spent less time interacting with the novel object compared with controls, indicating impaired short and long term retention.
Exp Paradigm: NA
Description: Male adnp het mice spend significantly less time sniffing the novel object compared to male wild type mice. female adnp het mice had normal novel object recognition, similar to wild type females
Exp Paradigm: Novel object recognition test: sexual dimorphism detected with female adnp mice showing normal object recognition and male mice being deficient
Description: Adnp het males and females show differences in transcript levels of multiple genes, including a significant decrease in male hippocampal fpr-rs3, and female hippocampal tubb1 in 2.7-3 week old mice and dysregulation the asd genes abcf3, adnp, akt1, bmp4, cdh17, iba1 (aif1), klf1, mtor and per1 in the spleen in 3 month old mice indicating sexual dimorphism.
Exp Paradigm: Gene expressions are normalized to hprt.
Description: Increased levels of elongation factor: eif4e transcripts were observed in male adnp het mice. no difference between females of the two genotypes was observable.
Exp Paradigm: NA
Description: Mutants show decrease in splenic adnp transcript levels compared with controls.
Exp Paradigm: Hprt was used as a validated reference transcript
Description: Adnp het male and female mice show decrease in adnp transcripts in the spleen. female mutants show a greater decrease in splenic adnp transcript than males indicating sexual dimorphism.
Exp Paradigm: Gene expressions are normalized to hprt.
Description: Female mutants show decrease in vglut1 gene expression in the cerebral cortex compared with controls. male mutants show decreased expression of vglut1 in the hippocampus compared with controls.
Exp Paradigm: Hippocampus; cerebral cortex
Description: Male mutants show decrease in hippocampal transcript levels of adcyap1 gene encoding pacap compared with controls. female mutants show decrease in hippocampal adcyap1r1 transcript levels at 5 months but not at 1 month compared with controls. female mutants show decrease in hippoccampal vipr1 expression at 1 month but not at 5 months compared with controls.
Exp Paradigm: NA
Description: Male and female mutants exposed to stress show decrease in time spent sniffing a mouse over a cup compared with controls.
Exp Paradigm: NA
Description: Female mutants exposed to stress show increase in time spent in the open arms compared with controls. increase in time spent in the closed arms is positively corelated with increase in cortisol levels.
Exp Paradigm: NA
Description: Stress challenged mutants show decrease in time spent exploring the novel object compared with controls.
Exp Paradigm: Fraction of time spent with the novel object in relation to the total time spent sniffing both novel and familiar objects is measured (d2 score)
Description: Increased eubacteriaceae, lactobacillus, bifidobacterium genus, mouse intestinal bacteroides, clostridium coccoides group; in males, anxiety, locomotion, social approach and social memory phenotypes correlated with fecal bifidobacterium genus load; no change in enterobacteriaceae, enterococcus genus, bacteroides/prevotella species, clostridium coccoides group, clostridium leptum group in male
Exp Paradigm: NA
16s rrna gene sequence analysis for identification of bacteria
Description: Decreased lactobacillus, clostridium leptum group in females; increased enterocosccus, clostridium coccoides in females; no change in eubacteriaceae, bifidobacterium genus, bacteroides, mouse intestinal bacteroides in female
Exp Paradigm: NA
16s rrna gene sequence analysis for identification of bacteria
Description: Tyr-males exhibiting nap correctable increases in print length and area vs. wt mice; both sexes exhibited a smaller front base of support, with male nap correction; sexual dimorphism
Exp Paradigm: CatWalk XT
Description: Tyr male mice showed increased grooming frequency and duration with males significantly more frequent than females; females showed increased grooming frequency only; sexual dimorphism
Description: Area under the curve of 3 vep major waveforms corresponding to 3 different stimulation intensities showed a significant genotype effect with nap reversal
Exp Paradigm: HMsERG LAB system
Description: Social recognition of naïve (not fostered/handled) tyr-mice was impaired in both sexes, differences were lost in treated cohort, possibly due to early handling/fostering
Description: Male tyr-mice exhibited increased total eubacterial load (eubv3), bifidobacterium genus (bif) and lactobacillus group (lacto), as well as decreased loads of enterobacteriaceae (entero); sexual dimorphism
Exp Paradigm: Fecal DNA was analyzed by qRT-PCR directed at bacterial 16S rRNA to obtain microbiota signatures
Description: Increased bacterial load of bif in female mice; sexual dimorphism
Exp Paradigm: Fecal DNA was analyzed by qRT-PCR directed at bacterial 16S rRNA to obtain microbiota signatures
Description: ~1.84-fold increase in at8 positive cells (pathological tau hyperphosphorylation) in the hippocampus of tyr-males and ~1.7-fold increase in the visual cortex; sexual dimorphism
Exp Paradigm: AT8+ staining
Description: Combining at8+at180 positive cells revealed a significant tyr genotype-increase in both sexes in both hippocampus and visual cortex
Exp Paradigm: AT8+AT180+ staining
