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Variants in ADD1 cause intellectual disability,corpus callosum dysgenesis,and ventriculomegaly in humans
Authors:Cai Qi  Irena Feng  Ana Rita Costa  Rita Pinto-Costa  Jennifer E Neil  Oana Caluseriu  Dong Li  Rebecca D Ganetzky  Charlotte Brasch-Andersen  Christina Fagerberg  Lars Kjærsgaard Hansen  Caleb Bupp  Colleen Clarke Muraresku  Xiangbin Ruan  Bowei Kang  Kaining Hu  Rong Zhong  Pedro Brites  Xiaochang Zhang
Institution:1. Department of Human Genetics, The University of Chicago, Chicago, IL;2. Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC) and Instituto de Inovação e Investigação em Saúde, University of Porto, Porto, Portugal;3. Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children’s Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA;4. Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada;5. Center for Applied Genomics, The Joseph Stokes Jr Research Institute, The Children''s Hospital of Philadelphia, Philadelphia, PA;6. Mitochondrial Medicine Frontier Program, Division of Human Genetics, The Children’s Hospital of Philadelphia, Philadelphia, PA;7. Department of Pediatrics, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;8. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark;9. Medical Genetics, Helen DeVos Children’s Hospital, Grand Rapids, MI;10. Neurolipid Biology, Instituto de Inovação e Investigação em Saúde, and Instituto de Biologia Molecular e Celular (IBMC), University of Porto, Porto, Portugal;11. Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT;12. The Neuroscience Institute, The University of Chicago, Chicago, IL
Abstract:PurposeAdducins interconnect spectrin and actin filaments to form polygonal scaffolds beneath the cell membranes and form ring-like structures in neuronal axons. Adducins regulate mouse neural development, but their function in the human brain is unknown.MethodsWe used exome sequencing to uncover ADD1 variants associated with intellectual disability (ID) and brain malformations. We studied ADD1 splice isoforms in mouse and human neocortex development with RNA sequencing, super resolution imaging, and immunoblotting. We investigated 4 variant ADD1 proteins and heterozygous ADD1 cells for protein expression and ADD1–ADD2 dimerization. We studied Add1 functions in vivo using Add1 knockout mice.ResultsWe uncovered loss-of-function ADD1 variants in 4 unrelated individuals affected by ID and/or structural brain defects. Three additional de novo copy number variations covering the ADD1 locus were associated with ID and brain malformations. ADD1 is highly expressed in the neocortex and the corpus callosum, whereas ADD1 splice isoforms are dynamically expressed between cortical progenitors and postmitotic neurons. Human variants impair ADD1 protein expression and/or dimerization with ADD2. Add1 knockout mice recapitulate corpus callosum dysgenesis and ventriculomegaly phenotypes.ConclusionOur human and mouse genetics results indicate that pathogenic ADD1 variants cause corpus callosum dysgenesis, ventriculomegaly, and/or ID.
Keywords:Adducin  Alternative splicing  Axon degeneration  Membrane-associated periodic ring-like structure (MPS)
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