Alternative titles; symbols
HGNC Approved Gene Symbol: ADNP
SNOMEDCT: 766824003;
Cytogenetic location: 20q13.13 Genomic coordinates (GRCh38) : 20:50,888,918-50,931,437 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.13 | Helsmoortel-van der Aa syndrome | 615873 | Autosomal dominant | 3 |
ADNP is a homeodomain-containing zinc finger protein with transcription factor activity that is essential for brain formation (Gozes, 2007; Mandel et al., 2007). ADNP interacts with components of the BAF complex, the eukaryotic equivalent of the SWI/SNF complex in yeast that is involved in the regulation of gene expression (summary by Helsmoortel et al., 2014). See, e.g., ARID1A (603024).
By screening for cDNAs encoding large proteins expressed in brain, Nagase et al. (1998) cloned ADNP, which they called KIAA0784. The predicted protein contains 1,073 amino acids. RT-PCR ELISA showed ubiquitous expression of ADNP, with highest levels in brain and ovary, followed by heart, lung, kidney, and testis.
By screening a fetal brain cDNA library with mouse Adnp, Zamostiano et al. (2001) cloned human ADNP. The predicted 1,102-amino acid protein has 9 zinc finger motifs, a proline-rich region, a bipartite nuclear localization signal, a partial homeobox domain, a glutaredoxin (GLRX; 600443) active site, and a leucine-rich nuclear export sequence. Northern blot analysis revealed ubiquitous expression of a 5.5-kb transcript, with highest levels in heart, skeletal muscle, kidney, and placenta. Within brain, expression was highest in cerebellum and cortex. Expression of ADNP was increased in tumor tissues.
Using fluorescence-tagged protein, Mandel and Gozes (2007) found that ADNP localized to the nucleus of transfected HEK293 cells.
Zamostiano et al. (2001) found that downregulation of ADNP by antisense oligonucleotides upregulated p53 (TP53; 191170) and reduced the viability of intestinal cancer cells by 90%. They proposed that ADNP is involved in maintaining cell survival, possibly by modulating p53.
By peptide digestion followed by mass spectrometric analysis of HEK293 cell immunoprecipitates, Mandel and Gozes (2007) found that fluorescence-tagged ADNP interacted with BRG1 (SMARCA4; 603254), BAF250A (ARID1A; 603024), and BAF170 (SMARCC2; 601734), which are components of the SWI/SNF chromatin remodeling complex. Domain analysis showed that the C-terminal domain of ADNP was required for its interaction with SWI/SNF proteins. Short hairpin RNAs that knocked down ADNP expression to 80%, but not to 50%, resulted in microtubule reorganization and changes in cell morphology, with reduced formation of cell processes and reduced cell number.
By quantitative RT-PCR, Dresner et al. (2011) found a high correlation between expression of ADNP2 (617422) and ADNP in postmortem normal human hippocampal specimens. This correlation was significantly reduced in hippocampus of schizophrenia patients, mirroring a disease-associated increase in ADNP2 transcripts. The correlation between ADNP2 and ADNP mRNA levels remained relatively higher in cortex of schizophrenia patients.
Ostapcuk et al. (2018) showed that ADNP interacts with the chromatin remodeler CHD4 (603277) and the chromatin architectural protein HP1 (604478) to form a stable complex, which they referred to as ChAHP. Besides mediating complex assembly, ADNP recognizes DNA motifs that specify binding of ChAHP to euchromatin. Genetic ablation of ChAHP components in mouse embryonic stem cells resulted in spontaneous differentiation concomitant with premature activation of lineage-specific genes and in a failure to differentiate towards the neuronal lineage. Molecularly, ChAHP-mediated repression is fundamentally different from canonical HP1-mediated silencing: HP1 proteins, in conjunction with histone H3 lysine-9 trimethylation (H3K9me3), are thought to assemble broad heterochromatin domains that are refractory to transcription. ChAHP-mediated repression, however, acts in a locally restricted manner by establishing inaccessible chromatin around its DNA-binding sites and does not depend on H3K9me3-modified nucleosomes. Ostapcuk et al. (2018) concluded that their results revealed that ADNP, via the recruitment of HP1 and CHD4, regulates the expression of genes that are crucial for maintaining distinct cellular states and assures accurate cell fate decisions upon external cues. Such a general role of ChAHP in governing cell fate plasticity may explain why ADNP mutations affect several organs and body functions and contribute to cancer progression. Ostapcuk et al. (2018) found that the integrity of the ChAHP complex is disrupted by nonsense mutations identified in patients with Helsmoortel-Van der Aa syndrome (615873), and this could be rescued by aminoglycosides that suppress translation termination.
Zamostiano et al. (2001) determined that the ADNP gene contains 5 exons and spans 40.6 kb. The last 3 exons are translated (Helsmoortel et al., 2014).
Using FISH, Zamostiano et al. (2001) mapped the ADNP gene to chromosome 20q12-q13.2, a region frequently amplified in neoplasias and associated with aggressive tumor growth.
In 10 unrelated patients with Helsmoortel-Van der Aa syndrome (HVDAS; 615873), Helsmoortel et al. (2014) identified 9 different de novo heterozygous truncating mutations in the ADNP gene (see, e.g., 611386.0001-611386.0005). The initial mutations were found by whole-exome sequencing, whereas additional mutations were found by direct analysis of the ADNP gene. The patients with MRD28 were ascertained from several cohorts totaling 5,776 unrelated patients with intellectual disability and/or autism spectrum disorder (ASD), thus accounting for 0.17% of these patients. All of the mutations occurred at the 3-prime end of the last exon of the ADNP gene and were predicted to result in the loss of at least the last 166 C-terminal residues, with escape from nonsense-mediated mRNA decay. Several of the mutations clustered in the stem of the same short hairpin, suggesting that the mutations may have resulted from a DNA-repair defect in this region. Available cells from 4 patients showed significantly increased levels of mutant mRNA compared to wildtype, suggesting deregulation of a negative expression feedback loop. Helsmoortel et al. (2014) noted that mutations in other SWI/SNF components of the BAF complex, such as SMARCB1 (601607) and ARID1B (614556), have been identified in patients with intellectual disability, and hypothesized that the ADNP mutations cause a dominant-negative effect on the recruitment of the BAF complex, resulting in deregulation of gene expression and a disruption of neuronal processes.
In 4 patients with intellectual disability and varying syndromic features, the Deciphering Developmental Disorders Study (2015) identified 3 de novo heterozygous mutations in the ADNP gene (611386.0006-611386.0008). Functional studies were not performed.
Van Dijck et al. (2019) reported the mutations in the ADNP gene in a worldwide cohort of 78 individuals with HVDAS, some of whom had previously been reported. The patients ranged in age from 1 to 40 years. There were no reports of consanguinity or affected sibs. Forty-six unique mutations were identified, of which 25 were nonsense and 21 were frameshift. Forty-three of the mutations were located in the last exon of the ADNP gene. Some mutations indicated mutation hotspots (see, e.g., 611386.0005, 611386.0009, 611386.0010). Sixty-eight mutations were confirmed to be de novo, 8 mutations were of unknown inheritance, and 2 C-terminal mutations were inherited.
Bend et al. (2019) performed genomewide DNA methylation analysis on peripheral blood DNA from 22 patients with HVDAS and identified 2 distinct episignatures caused by mutation in the ADNP gene. The first episignature (epi-ADNP-1) included approximately 6,000 mostly hypomethylated CpGs, and the second (epi-ADNP-2) included approximately 1,000 predominantly hypermethylated CpGs. The episignatures correlated with the location of the mutations, with epi-ADNP-1 mutations located outside nucleotides 2000 and 2340, and epi-ADNP-2 mutations located between nucleotides 2000 and 2340. The episignatures were enriched for genes involved in neuronal system development and function. Bend et al. (2019) showed that the DNA methylation signatures could aid in diagnosis.
Breen et al. (2020) evaluated gene expression in 17 individuals with HVDAS and 19 controls to determine if gene expression changes were predictable based on methylation status. Profound alterations in corresponding gene expression profiles were not observed. The absence of correlation between methylation and gene expression signatures and clinical manifestations led Breen et al. (2020) to caution against making phenotypic assumptions based on the blood-based methylation profile.
Breen et al. (2020) found that patients with class I mutations (located outside nucleotides 2000 and 2340) and class II mutations (located between nucleotides 2000 and 2340) had similar frequencies of impaired intellectual development, language impairment, attention-deficit hyperactivity disorder, and other medical problems. Individuals with class II mutations had a significantly longer delay in first walking independently, a higher prevalence of ASD, and a tendency towards increased self-injurious behavior.
Pinhasov et al. (2003) found that Adnp deletion in mice was embryonic lethal. Adnp -/- mice showed failure of cranial neural tube closure, increased Oct4 (POU5F1; 164177) expression, and absence of Pax6 (607108) expression.
By microarray analysis, Mandel et al. (2007) found that knockout of Adnp in mice upregulated genes involved in lipid transport, lytic vacuoles, and coagulation and downregulated genes involved in regulation of transcription, organogenesis, and neurogenesis. Promoter analysis revealed that genes upregulated by Adnp knockout were enriched in Pparg (601487)-, Hnf4 (HNF4A; 600281)-, and Hnf1 (TCF1; 142410)-binding sites, whereas downregulated genes were enriched in Zf5 (ZFP161; 602126)- and E2f (E2F1; 189971)-binding sites. Chromatin immunoprecipitation, bioinformatic, and coimmunoprecipitation analyses showed that Adnp bound chromatin and interacted with heterochromatin-1-alpha (CBX5; 604478).
In 2 unrelated children with Helsmoortel-Van der Aa syndrome (HVDAS; 615873), Helsmoortel et al. (2014) identified a de novo heterozygous 4-bp deletion (c.2491_2394delTTAA) in exon 5 of the ADNP gene, resulting in a frameshift and premature termination (Lys831IlefsTer81). The mutation, which was found by targeted analysis of the ADNP gene in both patients, was not present in the 1000 Genomes Project or Exome Sequencing Project databases, or in 1,728 unaffected individuals or 192 Belgian chromosomes.
In a Belgian child with Helsmoortel-Van der Aa syndrome (HVDAS; 615873), Helsmoortel et al. (2014) identified a de novo heterozygous 4-bp deletion (c.2496_2499delTAAA) in exon 5 of the ADNP gene, resulting in a frameshift and premature termination (Asp832LysfsTer80). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the 1000 Genomes Project or Exome Sequencing Project databases, or in 1,728 unaffected individuals or 192 Belgian chromosomes.
In a Belgian child with Helsmoortel-Van der Aa syndrome (HVDAS; 615873), Helsmoortel et al. (2014) identified a de novo heterozygous c.1211C-A transversion in exon 5 of the ADNP gene, resulting in a ser404-to-ter (S404X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the 1000 Genomes Project or Exome Sequencing Project databases, or in 1,728 unaffected individuals or 192 Belgian chromosomes.
In a Belgian child with Helsmoortel-Van der Aa syndrome (HVDAS; 615873), Helsmoortel et al. (2014) identified a de novo heterozygous 1-bp deletion (c.2808delC) in exon 5 of the ADNP gene, resulting in a frameshift and premature termination (Tyr936Ter). The mutation, which was found by targeted analysis of the ADNP gene, was not present in the 1000 Genomes Project or Exome Sequencing Project databases, or in 1,728 unaffected individuals or 192 Belgian chromosomes.
In a Swedish child with Helsmoortel-Van der Aa syndrome (HVDAS; 615873), Helsmoortel et al. (2014) identified a de novo heterozygous c.2157C-G transversion in exon 5 of the ADNP gene, resulting in a tyr719-to-ter (Y719X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the 1000 Genomes Project or Exome Sequencing Project databases, or in 1,728 unaffected individuals or 192 Belgian chromosomes.
By whole-exome sequencing in a 6-year-old girl with HVDAS, Pescosolido et al. (2014) identified a de novo heterozygous Y719X mutation in the ADNP gene. The mutation was confirmed by Sanger sequencing.
In a worldwide cohort of 78 patients with HVDAS, Van Dijck et al. (2019) identified the c.2157C-G mutation in 6 patients. A different mutation at the same nucleotide resulted in a Y719X substitution (611386.0009), indicating that this is a mutation hotspot.
In 2 patients, a male and a female, with Helsmoortel-Van der Aa syndrome (HVDAS; 615873), the Deciphering Developmental Disorders Study (2015) identified a heterozygous de novo 4-bp deletion of TTTA nucleotides beginning at chromosome coordinate g.49,508,751 in the ADNP gene (chr20.49,508,751delTTTA, GRCh37), resulting in frameshift. The authors described the mutation as an indel (CTTTATTTA/CTTTA) between coordinates g.49,508,751 and g.49,508,760. Aside from global developmental delay, the patients had different clinical features.
In a male patient (DECIPHER ID 258927) with intellectual disability, plagiocephaly, obesity, and inguinal hernia (HVDAS; 615873), the Deciphering Developmental Disorders Study (2015) identified a heterozygous de novo 1-bp insertion of a T at chromosome coordinate g.49,509,094 in the ADNP gene (chr20.49,509,094insT, GRCh37). The authors described the mutation as an indel (GT/GTT) between coordinates g.49,509,094 and g.49,509,097.
In a male patient with Helsmoortel-Van der Aa syndrome (HVDAS; 615873), the Deciphering Developmental Disorders Study (2015) identified a heterozygous de novo 2-bp deletion of a TT at chromosome coordinate g.49,510,027 in the ADNP gene (chr20.49,510,027delTT). The authors described the mutation as an indel (CTTT/CT) between coordinates g.49,510,027 and g.49,510,031. The patient had global developmental delay, generalized neonatal hypotonia, bilateral ptosis, plagiocephaly, first-degree microtia, and respiratory distress.
From a worldwide cohort of 78 patients with Helsmoortel-Van der Aa syndrome (HVDAS; 615873), Van Dijck et al. (2019) identified a c.2157C-A transversion in the ADNP gene, resulting in a tyr719-to-ter (Y719X) substitution, in 3 patients. A different mutation at the same nucleotide resulted in a Y719X substitution (611386.0005), indicating that this is a mutation hotspot.
From a worldwide cohort of 78 patients with Helsmoortel-Van der Aa syndrome (HVDAS; 615873), Van Dijck et al. (2019) identified a 4-bp deletion in the ADNP gene (c.2496_2499delTAAA), resulting in a frameshift and premature termination (Asn832LysfsTer81), in 10 patients. The mutation had previously been identified in a patient by Helsmoortel et al. (2014).
From a worldwide cohort of 78 patients with Helsmoortel-Van der Aa syndrome (HVDAS; 615873), Van Dijck et al. (2019) identified a 1-bp duplication (c.2156dupT) in the ADNP gene, resulting in a tyr719-to-ter (Y719X) substitution, in 8 patients. The authors identified 2 other mutations in the ADNP gene in patients with HVDAS that resulted in a Y719X substitution (see 611386.0005 and 611386.0009). This mutation had previously been identified in a patient by Helsmoortel et al. (2014).
Bend, E. G., Aref-Eshghi, E., Everman, D. B., Rogers, R. C., Cathey, S. S., Prijoles, E. J., Lyons, M. J., Davis, H., Clarkson, K., Gripp, K. W., Li, D., Bhoj, E., and 12 others. Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome. Clin. Epigenet. 11: 64, 2019. Note: Electronic Article. [PubMed: 31029150] [Full Text: https://doi.org/10.1186/s13148-019-0658-5]
Breen, M. S., Garg, P., Tang, L., Mendonca, D., Levy, T., Barbosa, M., Arnett, A. B., Kurtz-Nelson, E., Agolini, E., Battaglia, A., Chiocchetti, A. G., Freitag, C. M., and 17 others. Episignatures stratifying Helsmoortel-Van Der Aa syndrome show modest correlation with phenotype. Am. J. Hum. Genet. 107: 555-563, 2020. [PubMed: 32758449] [Full Text: https://doi.org/10.1016/j.ajhg.2020.07.003]
Deciphering Developmental Disorders Study. Large-scale discovery of novel genetic causes of developmental disorders. Nature 519: 223-228, 2015. [PubMed: 25533962] [Full Text: https://doi.org/10.1038/nature14135]
Dresner, E., Agam, G., Gozes, I. Activity-dependent neuroprotective protein (ADNP) expression level is correlated with the expression of the sister protein ADNP2: deregulation in schizophrenia. Europ. Neuropsychopharmacol. 21: 355-361, 2011. [PubMed: 20598862] [Full Text: https://doi.org/10.1016/j.euroneuro.2010.06.004]
Gozes, I. Activity-dependent neuroprotective protein: from gene to drug candidate. Pharm. Ther. 114: 146-154, 2007. [PubMed: 17363064] [Full Text: https://doi.org/10.1016/j.pharmthera.2007.01.004]
Helsmoortel, C., Vulto-van Silfhout, A. T., Coe, B. P., Vandeweyer, G., Rooms, L., van den Ende, J., Schuurs-Hoeijmakers, J. H. M., Marcelis, C. L., Willemsen, M. H., Vissers, L. E. L. M., Yntema, H. G., Bakshi, M., and 13 others. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nature Genet. 46: 380-384, 2014. [PubMed: 24531329] [Full Text: https://doi.org/10.1038/ng.2899]
Mandel, S., Gozes, I. Activity-dependent neuroprotective protein constitutes a novel element in the SWI/SNF chromatin remodeling complex. J. Biol. Chem. 282: 34448-34456, 2007. [PubMed: 17878164] [Full Text: https://doi.org/10.1074/jbc.M704756200]
Mandel, S., Rechavi, G., Gozes, I. Activity-dependent neuroprotective protein (ADNP) differentially interacts with chromatin to regulate genes essential for embryogenesis. Dev. Biol. 303: 814-824, 2007. [PubMed: 17222401] [Full Text: https://doi.org/10.1016/j.ydbio.2006.11.039]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 277-286, 1998. [PubMed: 9872452] [Full Text: https://doi.org/10.1093/dnares/5.5.277]
Ostapcuk, V., Mohn, F., Carl, S. H., Basters, A., Hess, D., Iesmantavicius, V., Lampersberger, L., Flemr, M., Pandey, A., Thoma, N. H., Betschinger, J., Buhler, M. Activity-dependent neuroprotective protein recruits HP1 and CHD4 to control lineage-specifying genes. Nature 557: 739-743, 2018. [PubMed: 29795351] [Full Text: https://doi.org/10.1038/s41586-018-0153-8]
Pescosolido, M. F., Schwede, M., Johnson Harrison, A., Schmidt, M., Gamsiz, E. D., Chen, W. S., Donahue, J. P., Shur, N., Jerskey, B. A., Phornphutkul, C., Morrow, E. M. Expansion of the clinical phenotype associated with mutations in activity-dependent neuroprotective protein. J. Med. Genet. 51: 587-589, 2014. [PubMed: 25057125] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102444]
Pinhasov, A., Mandel, S., Torchinsky, A., Giladi, E., Pittel, Z., Goldsweig, A. M., Servoss, S. J., Brenneman, D. E., Gozes, I. Activity-dependent neuroprotective protein: a novel gene essential for brain formation. Brain Res. Dev. Brain Res. 144: 83-90, 2003. [PubMed: 12888219] [Full Text: https://doi.org/10.1016/s0165-3806(03)00162-7]
Van Dijck, A., Vulto-van Silfhout, A. T., Cappuyns, E., van der Werf,, I M., Mancini, G. M., Tzschach, A., Bernier, R., Gozes, I., Eichler, E. E., Romano, C., Lindstrand, A., Nordgren, A., and 9 others. Clinical presentation of a complex neurodevelopmental disorder caused by mutations in ADNP. Biol. Psychiatry 85: 287-297, 2019. [PubMed: 29724491] [Full Text: https://doi.org/10.1016/j.biopsych.2018.02.1173]
Zamostiano, R., Pinhasov, A., Gelber, E., Steingart, R. A., Seroussi, E., Giladi, E., Bassan, M., Wollman, Y., Eyre, H. J., Mulley, J. C., Brenneman, D. E., Gozes, I. Cloning and characterization of the human activity-dependent neuroprotective protein. J. Biol. Chem. 276: 708-714, 2001. [PubMed: 11013255] [Full Text: https://doi.org/10.1074/jbc.M007416200]