Variants in ADD1 cause intellectual disability, corpus callosum dysgenesis, and ventriculomegaly in humans.

Autor:	Qi C; Department of Human Genetics, The University of Chicago, Chicago, IL., Feng I; Department of Human Genetics, The University of Chicago, Chicago, IL., Costa AR; Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC) and Instituto de Inovação e Investigação em Saúde, University of Porto, Porto, Portugal., Pinto-Costa R; Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC) and Instituto de Inovação e Investigação em Saúde, University of Porto, Porto, Portugal., Neil JE; Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA., Caluseriu O; Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada., Li D; Center for Applied Genomics, The Joseph Stokes Jr Research Institute, The Children's Hospital of Philadelphia, Philadelphia, PA., Ganetzky RD; Mitochondrial Medicine Frontier Program, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Brasch-Andersen C; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark., Fagerberg C; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark., Hansen LK; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark., Bupp C; Medical Genetics, Helen DeVos Children's Hospital, Grand Rapids, MI., Muraresku CC; Mitochondrial Medicine Frontier Program, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Ruan X; Department of Human Genetics, The University of Chicago, Chicago, IL., Kang B; Department of Human Genetics, The University of Chicago, Chicago, IL., Hu K; Department of Human Genetics, The University of Chicago, Chicago, IL., Zhong R; Department of Human Genetics, The University of Chicago, Chicago, IL., Brites P; Neurolipid Biology, Instituto de Inovação e Investigação em Saúde, and Instituto de Biologia Molecular e Celular (IBMC), University of Porto, Porto, Portugal., Bhoj EJ; Center for Applied Genomics, The Joseph Stokes Jr Research Institute, The Children's Hospital of Philadelphia, Philadelphia, PA., Hill RS; Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA., Falk MJ; Mitochondrial Medicine Frontier Program, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Hakonarson H; Center for Applied Genomics, The Joseph Stokes Jr Research Institute, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA., Kahle KT; Departments of Neurosurgery, Pediatrics, and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT., Sousa MM; Nerve Regeneration Group, Instituto de Biologia Molecular e Celular (IBMC) and Instituto de Inovação e Investigação em Saúde, University of Porto, Porto, Portugal. Electronic address: msousa@ibmc.up.pt., Walsh CA; Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA. Electronic address: christopher.walsh@childrens.harvard.edu., Zhang X; Department of Human Genetics, The University of Chicago, Chicago, IL; The Neuroscience Institute, The University of Chicago, Chicago, IL. Electronic address: xczhang@uchicago.edu.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2022 Feb; Vol. 24 (2), pp. 319-331. Date of Electronic Publication: 2021 Nov 30.
DOI:	10.1016/j.gim.2021.09.014
Abstrakt:	Purpose: Adducins 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. Methods: We 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. Results: We 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. Conclusion: Our human and mouse genetics results indicate that pathogenic ADD1 variants cause corpus callosum dysgenesis, ventriculomegaly, and/or ID. Competing Interests: Conflict of Interest R.D.G receives consulting fees from Minovia Therapeutics. All other authors declare no conflicts of interest. (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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