ILANIT 2020

Discovery of autism/intellectual disability somatic mutations in Alzheimerss brains

Yanina Ivashko Pachima 1 Adva Hadar 1 Iris Grigg 1 Vlasta Korenková 2 Oxana Kapitansky 1 Gidon Karmon 1 C. Laura Sayas 4 Michael Gershovits 3 Mohiuddin Mohiuddin 5 Christopher E. Pearson 5 R. Frank Kooy 6 Johannes Attems 7 David Gurwitz 1 Illana Gozes 1
1The Lily and Avraham Gildor Chair for the Investigation of Growth Factors; The Elton Laboratory for Neuroendocrinology; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super, Tel Aviv University, Israel
2Institute of Biotechnology Cas, Biocev, Czech Republic
3The Nancy & Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Israel
4Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, Spain
5Department of Genetics, The Hospital for Sick Children, University of Toronto, Canada
6Department of Medical Genetics, University of Antwerp, Belgium
7Institute of Neuroscience and Institute of Ageing, Newcastle University, UK

Alzehimer’s disease(AD) is one of the greatest medical challenges that face this century, with increasing prevalence and costs worldwide .With 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. We propose a paradigm-shifting concept in the perception of AD whereby accumulating mosaic somatic mutations promote brain pathology.









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