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Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

ABSTRACT: De novo mutated ADNP is a most prevalent gene driving syndromic autism with intellectual disability. Using droplet digital PCR and RNA sequencing we identified somatic mutations in ADNP and in other genes in the olfactory bulb and hipocampi of Alzheimer's disease (AD) patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113524 | GEO | 2019/11/04

REPOSITORIES: GEO

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Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study.

Project description:With Alzheimer's disease (AD) exhibiting reduced ability of neural stem cell renewal, we hypothesized that de novo mutations controlling embryonic development, in the form of brain somatic mutations instigate the disease. A leading gene presenting heterozygous dominant de novo autism-intellectual disabilities (ID) causing mutations is activity-dependent neuroprotective protein (ADNP), with intact ADNP protecting against AD-tauopathy. We discovered a genomic autism ADNP mutation (c.2188C>T) in postmortem AD olfactory bulbs and hippocampi. RNA-Seq of olfactory bulbs also identified a novel ADNP hotspot mutation, c.2187_2188insA. Altogether, 665 mutations in 596 genes with 441 mutations in AD patients (389 genes, 38% AD-exclusive mutations) and 104 genes presenting disease-causing mutations (OMIM) were discovered. OMIM AD mutated genes converged on cytoskeletal mechanisms, autism and ID causing mutations (about 40% each). The number and average frequencies of AD-related mutations per subject were higher in AD subjects compared to controls. RNA-seq datamining (hippocampus, dorsolateral prefrontal cortex, fusiform gyrus and superior frontal gyrus-583 subjects) yielded similar results. Overlapping all tested brain areas identified unique and shared mutations, with ADNP singled out as a gene associated with autism/ID/AD and presenting several unique aging/AD mutations. The large fusiform gyrus library (117 subjects) with high sequencing coverage correlated the c.2187_2188insA ADNP mutation frequency to Braak stage (tauopathy) and showed more ADNP mutations in AD specimens. In cell cultures, the ADNP-derived snippet NAP inhibited mutated-ADNP-microtubule (MT) toxicity and enhanced Tau-MT association. We propose a paradigm-shifting concept in the perception of AD whereby accumulating mosaic somatic mutations promote brain pathology.

| S-EPMC8159740 | biostudies-literature

Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

Project description:Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

| PRJNA451437 | ENA

Transcription profiling of mouse ADNP knockout vs wild type

Project description:The putative transcription factor, activity-dependent neuroprotective protein (ADNP) is a zinc finger and homeodomain - like profile containing protein. ADNP knockout mice die at day 9 of gestation. To reveal ADNP-associated pathways, a 22,690- Affymetrix probe array was used on ADNP knockout and control embryos. References:; Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide. J Neurochem. 1999 Mar;72(3):1283-93. PMID: 10037502 [PubMed - indexed for MEDLINE]; Cloning and characterization of the human activity-dependent neuroprotective protein. J Biol Chem. 2001 Jan 5;276(1):708-14. PMID: 11013255 [PubMed - indexed for MEDLINE]; Activity-dependent neuroprotective protein: a novel gene essential for brain formation. Brain Res Dev Brain Res. 2003 Aug 12;144(1):83-90. PMID: 12888219 [PubMed - indexed for MEDLINE] Experiment Overall Design: To identify downstream target genes of ADNP, we examined global gene expression profiles of whole E9 knockout embryos (KO - ADNP -l-), their wild-type (WT - ADNP +l+ ) and their heterozygous (H - ADNP âl+ ) littermates, using the Affymetrix Murine Genome 430A oligonucleotide microarrays. Gestation day 9 was chosen as it is the period at which embryos lacking ADNP exhibit distinct morphological and developmental changes prior to degeneration and in uterus absorption. Total RNA was extracted from four ADNP knockout embryos, four normal embryos and six heterozygous embryos. A pool of two genotype identical littermates was used on seven different arrays (pooling of two embryos was necessary to obtain enough RNA on each of the gene microarrays).

2008-06-12 | E-GEOD-4068 | biostudies-arrayexpress

ADNP suppresses R-loops at its binding sites

Project description:We have identified ADNP as an R-loop regulator using a proximity-dependent labeling system. We find that ADNP is necessary to suppress R-loops at its binding sites, and that deletion of the ADNP homeodomain reduces ADNP binding to chromatin and results in R-loop accumulation.

2021-11-15 | GSE171401 | GEO

Phosphoproteomic analysis of ADNP-mutant mice

Project description:We report age-differential synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIa hyperactivity in Adnp-mutant mice. These mice show impaired and inflexible contextual learning and memory along with social and anxiety-related deficits in adults, long after the juvenile-stage decrease of ADNP protein levels to ~10% of the newborn level. Adnp-mutant mice show abnormally enhanced long-term potentiation in adults but not in juveniles. This is accompanied by CaMKIIa hyperactivity involving increased baseline autophosphorylation and altered phosphorylation of CaMKIIa substrates, as revealed by unbiased proteomic analyses.

2023-07-11 | PXD037325 | Pride

Transcriptome analysis of Adnp-heterozygous mice in the hippocampus

Project description:ADNP syndrome, involving the ADNP transcription factor in the SWI/SNF chromatin-remodeling complex, is characterized by developmental delay, intellectual disability, and autism spectrum disorders (ASD). In ASD, ADNP is a highly penetrant risk gene, accounting for ~0.17% cases. Although Adnp-haploinsufficient mice display various phenotypic deficits, the underlying synaptic mechanisms are poorly understood. Here we report age-differential synaptic plasticity deficits associated with cognitive inflexibility and CaMKIIα hyperactivity in Adnp-mutant mice. These mice show impaired and inflexible contextual learning and memory additional to social and anxiety-related deficits in adults long after a marked decrease in ADNP protein levels to ~10% of newborn levels in juveniles. In addition, Adnp-mutant adults show abnormally enhanced long-term potentiation in adults but not in juveniles. This accompanies CaMKIIα hyperactivity involving increased baseline autophosphorylation, as revealed by unbiased proteomic analyses. Therefore, ADNP haploinsufficiency in mice leads to cognitive inflexibility involving altered synaptic plasticity and signaling in adults long after a marked decrease in Adnp expression in juveniles.

2023-07-11 | GSE213354 | GEO

Changes in gene expression following ADNP knockout

2007-01-09 | GSE4068 | GEO

ChIP-seq of ADNP and TRIM28 in the U2OS cell line (Human Bone Osteosarcoma Epithelial Cells)

Project description:In order to investigate the functions of the zinc finger transcription regulator ZMYM2 and the different types of ZMYM2 binding complex with TRIM28 or ADNP, we generated the ChIP-seq data of ADNP or TRIM28 in U2OS cells.

2023-06-01 | E-MTAB-12292 | biostudies-arrayexpress

SNP arrays to confirm X-linkage in a family with idiopathic intellectual disability

Project description:L061 family with idiopathic non-syndromic intellectual disability remained unsolved after targeted screening of ID-related genes, array-CGH and exome sequencing. In order to perform custom tandem repeat screening on the X chromosome by long read single molecule sequencing, X-linkage needed to be confirmed by SNP arrays.

2017-12-01 | E-MTAB-5903 | biostudies-arrayexpress

Episignatures stratifying ADNP syndrome show modest correlation with phenotype [Methylation]

Project description:We conducted an independent study on 24 individuals with ADNP syndrome and replicated the existence of the two mutation-dependent ADNP episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of ADNP syndrome.

2020-06-14 | GSE152427 | GEO

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