title: Dysfunctional ADAM22 implicated in progressive encephalopathy with cortical atrophy and epilepsy.
abstract: OBJECTIVE
  To identify the molecular genetic basis of a syndrome characterized by rapidly progressing cerebral atrophy, intractable seizures, and intellectual disability.
  
  
  METHODS
  We performed exome sequencing in the proband and whole-genome single nucleotide polymorphism genotyping (copy number variant analysis) in the proband-parent trio. We used heterologous expression systems to study the functional consequences of identified mutations.
  
  
  RESULTS
  The search for potentially deleterious recessive or de novo variants yielded compound heterozygous missense (c.1202G>A, p.Cys401Tyr) and frameshift deletion (c.2396delG, p.Ser799IlefsTer96) mutations in ADAM22, which encodes a postsynaptic receptor for LGI1. The deleterious effect of the mutations was observed in cell surface binding and immunoprecipitation assays, which revealed that both mutant proteins failed to bind to LGI1. Furthermore, immunoprecipitation assays showed that the frameshift mutant ADAM22 also did not bind to the postsynaptic scaffolding protein PSD-95.
  
  
  CONCLUSIONS
  The mutations identified abolish the LGI1-ADAM22 ligand-receptor complex and are thus a likely primary cause of the proband's epilepsy syndrome, which is characterized by unusually rapidly progressing cortical atrophy starting at 3-4 months of age. These findings are in line with the implicated role of the LGI1-ADAM22 complex as a key player in nervous system development, specifically in functional maturation of postnatal synapses. Because the frameshift mutation affects an alternatively spliced exon with highest expression in postnatal brain, the combined effect of the mutations is likely to be hypomorphic rather than complete loss of function. This is compatible with the longer survival of the patient compared to Lgi1 (-/-) and Adam22 (-/-) mice, which develop lethal seizures during the first postnatal weeks.
authors.affiliation: Institute for Molecular Medicine Finland (M.M., A.P.), Neuroscience Center (M.M., A.L., A.-E.L.), and Research Programs Unit, Molecular Neurology (M.M., A.-K.A., A.L., A.-E.L.), University of Helsinki, Finland; Folkhälsan Institute of Genetics (M.M., A.-K.A., A.L., A.-E.L.), Helsinki, Finland; Division of Membrane Physiology (Y.F., M.F.), Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan; Department of Physiological Sciences (Y.F., M.F.), School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan; Medical and Clinical Genetics (A.-K.A.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Analytic and Translational Genetics Unit (A.P.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Program in Medical and Population Genetics (A.P.) and Stanley Center for Psychiatric Research (A.P.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Program in Genetics and Genomics (A.P.), Biological and Biomedical Sciences, Harvard Medical School, Boston, MA; Wellcome Trust Sanger Institute (A.P.), Wellcome Trust Genome Campus, Hinxton, United Kingdom; Psychiatric & Neurodevelopmental Genetics Unit (A.P.), Department of Psychiatry, and Department of Neurology (A.P.), Massachusetts General Hospital, Boston, MA; Department of Pediatric Neurology (H.P., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Radiology (L.V.), HUS Medical Imaging Center, Helsinki, Finland; and Family Federation of Finland (M.S.), Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Muona
authors.affiliation: Institute for Molecular Medicine Finland (M.M., A.P.), Neuroscience Center (M.M., A.L., A.-E.L.), and Research Programs Unit, Molecular Neurology (M.M., A.-K.A., A.L., A.-E.L.), University of Helsinki, Finland; Folkhälsan Institute of Genetics (M.M., A.-K.A., A.L., A.-E.L.), Helsinki, Finland; Division of Membrane Physiology (Y.F., M.F.), Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan; Department of Physiological Sciences (Y.F., M.F.), School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan; Medical and Clinical Genetics (A.-K.A.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Analytic and Translational Genetics Unit (A.P.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Program in Medical and Population Genetics (A.P.) and Stanley Center for Psychiatric Research (A.P.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Program in Genetics and Genomics (A.P.), Biological and Biomedical Sciences, Harvard Medical School, Boston, MA; Wellcome Trust Sanger Institute (A.P.), Wellcome Trust Genome Campus, Hinxton, United Kingdom; Psychiatric & Neurodevelopmental Genetics Unit (A.P.), Department of Psychiatry, and Department of Neurology (A.P.), Massachusetts General Hospital, Boston, MA; Department of Pediatric Neurology (H.P., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Radiology (L.V.), HUS Medical Imaging Center, Helsinki, Finland; and Family Federation of Finland (M.S.), Helsinki, Finland.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fukata
authors.affiliation: Institute for Molecular Medicine Finland (M.M., A.P.), Neuroscience Center (M.M., A.L., A.-E.L.), and Research Programs Unit, Molecular Neurology (M.M., A.-K.A., A.L., A.-E.L.), University of Helsinki, Finland; Folkhälsan Institute of Genetics (M.M., A.-K.A., A.L., A.-E.L.), Helsinki, Finland; Division of Membrane Physiology (Y.F., M.F.), Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan; Department of Physiological Sciences (Y.F., M.F.), School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan; Medical and Clinical Genetics (A.-K.A.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Analytic and Translational Genetics Unit (A.P.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Program in Medical and Population Genetics (A.P.) and Stanley Center for Psychiatric Research (A.P.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Program in Genetics and Genomics (A.P.), Biological and Biomedical Sciences, Harvard Medical School, Boston, MA; Wellcome Trust Sanger Institute (A.P.), Wellcome Trust Genome Campus, Hinxton, United Kingdom; Psychiatric & Neurodevelopmental Genetics Unit (A.P.), Department of Psychiatry, and Department of Neurology (A.P.), Massachusetts General Hospital, Boston, MA; Department of Pediatric Neurology (H.P., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Radiology (L.V.), HUS Medical Imaging Center, Helsinki, Finland; and Family Federation of Finland (M.S.), Helsinki, Finland.
authors.forename: Anna-Kaisa
authors.initials: AK
authors.lastname: Anttonen
authors.affiliation: Institute for Molecular Medicine Finland (M.M., A.P.), Neuroscience Center (M.M., A.L., A.-E.L.), and Research Programs Unit, Molecular Neurology (M.M., A.-K.A., A.L., A.-E.L.), University of Helsinki, Finland; Folkhälsan Institute of Genetics (M.M., A.-K.A., A.L., A.-E.L.), Helsinki, Finland; Division of Membrane Physiology (Y.F., M.F.), Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan; Department of Physiological Sciences (Y.F., M.F.), School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan; Medical and Clinical Genetics (A.-K.A.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Analytic and Translational Genetics Unit (A.P.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Program in Medical and Population Genetics (A.P.) and Stanley Center for Psychiatric Research (A.P.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Program in Genetics and Genomics (A.P.), Biological and Biomedical Sciences, Harvard Medical School, Boston, MA; Wellcome Trust Sanger Institute (A.P.), Wellcome Trust Genome Campus, Hinxton, United Kingdom; Psychiatric & Neurodevelopmental Genetics Unit (A.P.), Department of Psychiatry, and Department of Neurology (A.P.), Massachusetts General Hospital, Boston, MA; Department of Pediatric Neurology (H.P., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Radiology (L.V.), HUS Medical Imaging Center, Helsinki, Finland; and Family Federation of Finland (M.S.), Helsinki, Finland.
authors.forename: Anni
authors.initials: A
authors.lastname: Laari
authors.affiliation: Institute for Molecular Medicine Finland (M.M., A.P.), Neuroscience Center (M.M., A.L., A.-E.L.), and Research Programs Unit, Molecular Neurology (M.M., A.-K.A., A.L., A.-E.L.), University of Helsinki, Finland; Folkhälsan Institute of Genetics (M.M., A.-K.A., A.L., A.-E.L.), Helsinki, Finland; Division of Membrane Physiology (Y.F., M.F.), Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan; Department of Physiological Sciences (Y.F., M.F.), School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan; Medical and Clinical Genetics (A.-K.A.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Analytic and Translational Genetics Unit (A.P.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Program in Medical and Population Genetics (A.P.) and Stanley Center for Psychiatric Research (A.P.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Program in Genetics and Genomics (A.P.), Biological and Biomedical Sciences, Harvard Medical School, Boston, MA; Wellcome Trust Sanger Institute (A.P.), Wellcome Trust Genome Campus, Hinxton, United Kingdom; Psychiatric & Neurodevelopmental Genetics Unit (A.P.), Department of Psychiatry, and Department of Neurology (A.P.), Massachusetts General Hospital, Boston, MA; Department of Pediatric Neurology (H.P., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Radiology (L.V.), HUS Medical Imaging Center, Helsinki, Finland; and Family Federation of Finland (M.S.), Helsinki, Finland.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: Institute for Molecular Medicine Finland (M.M., A.P.), Neuroscience Center (M.M., A.L., A.-E.L.), and Research Programs Unit, Molecular Neurology (M.M., A.-K.A., A.L., A.-E.L.), University of Helsinki, Finland; Folkhälsan Institute of Genetics (M.M., A.-K.A., A.L., A.-E.L.), Helsinki, Finland; Division of Membrane Physiology (Y.F., M.F.), Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan; Department of Physiological Sciences (Y.F., M.F.), School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan; Medical and Clinical Genetics (A.-K.A.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Analytic and Translational Genetics Unit (A.P.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Program in Medical and Population Genetics (A.P.) and Stanley Center for Psychiatric Research (A.P.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Program in Genetics and Genomics (A.P.), Biological and Biomedical Sciences, Harvard Medical School, Boston, MA; Wellcome Trust Sanger Institute (A.P.), Wellcome Trust Genome Campus, Hinxton, United Kingdom; Psychiatric & Neurodevelopmental Genetics Unit (A.P.), Department of Psychiatry, and Department of Neurology (A.P.), Massachusetts General Hospital, Boston, MA; Department of Pediatric Neurology (H.P., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Radiology (L.V.), HUS Medical Imaging Center, Helsinki, Finland; and Family Federation of Finland (M.S.), Helsinki, Finland.
authors.forename: Helena
authors.initials: H
authors.lastname: Pihko
authors.affiliation: Institute for Molecular Medicine Finland (M.M., A.P.), Neuroscience Center (M.M., A.L., A.-E.L.), and Research Programs Unit, Molecular Neurology (M.M., A.-K.A., A.L., A.-E.L.), University of Helsinki, Finland; Folkhälsan Institute of Genetics (M.M., A.-K.A., A.L., A.-E.L.), Helsinki, Finland; Division of Membrane Physiology (Y.F., M.F.), Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan; Department of Physiological Sciences (Y.F., M.F.), School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan; Medical and Clinical Genetics (A.-K.A.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Analytic and Translational Genetics Unit (A.P.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Program in Medical and Population Genetics (A.P.) and Stanley Center for Psychiatric Research (A.P.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Program in Genetics and Genomics (A.P.), Biological and Biomedical Sciences, Harvard Medical School, Boston, MA; Wellcome Trust Sanger Institute (A.P.), Wellcome Trust Genome Campus, Hinxton, United Kingdom; Psychiatric & Neurodevelopmental Genetics Unit (A.P.), Department of Psychiatry, and Department of Neurology (A.P.), Massachusetts General Hospital, Boston, MA; Department of Pediatric Neurology (H.P., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Radiology (L.V.), HUS Medical Imaging Center, Helsinki, Finland; and Family Federation of Finland (M.S.), Helsinki, Finland.
authors.forename: Tuula
authors.initials: T
authors.lastname: Lönnqvist
authors.affiliation: Institute for Molecular Medicine Finland (M.M., A.P.), Neuroscience Center (M.M., A.L., A.-E.L.), and Research Programs Unit, Molecular Neurology (M.M., A.-K.A., A.L., A.-E.L.), University of Helsinki, Finland; Folkhälsan Institute of Genetics (M.M., A.-K.A., A.L., A.-E.L.), Helsinki, Finland; Division of Membrane Physiology (Y.F., M.F.), Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan; Department of Physiological Sciences (Y.F., M.F.), School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan; Medical and Clinical Genetics (A.-K.A.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Analytic and Translational Genetics Unit (A.P.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Program in Medical and Population Genetics (A.P.) and Stanley Center for Psychiatric Research (A.P.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Program in Genetics and Genomics (A.P.), Biological and Biomedical Sciences, Harvard Medical School, Boston, MA; Wellcome Trust Sanger Institute (A.P.), Wellcome Trust Genome Campus, Hinxton, United Kingdom; Psychiatric & Neurodevelopmental Genetics Unit (A.P.), Department of Psychiatry, and Department of Neurology (A.P.), Massachusetts General Hospital, Boston, MA; Department of Pediatric Neurology (H.P., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Radiology (L.V.), HUS Medical Imaging Center, Helsinki, Finland; and Family Federation of Finland (M.S.), Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Valanne
authors.affiliation: Institute for Molecular Medicine Finland (M.M., A.P.), Neuroscience Center (M.M., A.L., A.-E.L.), and Research Programs Unit, Molecular Neurology (M.M., A.-K.A., A.L., A.-E.L.), University of Helsinki, Finland; Folkhälsan Institute of Genetics (M.M., A.-K.A., A.L., A.-E.L.), Helsinki, Finland; Division of Membrane Physiology (Y.F., M.F.), Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan; Department of Physiological Sciences (Y.F., M.F.), School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan; Medical and Clinical Genetics (A.-K.A.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Analytic and Translational Genetics Unit (A.P.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Program in Medical and Population Genetics (A.P.) and Stanley Center for Psychiatric Research (A.P.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Program in Genetics and Genomics (A.P.), Biological and Biomedical Sciences, Harvard Medical School, Boston, MA; Wellcome Trust Sanger Institute (A.P.), Wellcome Trust Genome Campus, Hinxton, United Kingdom; Psychiatric & Neurodevelopmental Genetics Unit (A.P.), Department of Psychiatry, and Department of Neurology (A.P.), Massachusetts General Hospital, Boston, MA; Department of Pediatric Neurology (H.P., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Radiology (L.V.), HUS Medical Imaging Center, Helsinki, Finland; and Family Federation of Finland (M.S.), Helsinki, Finland.
authors.forename: Mirja
authors.initials: M
authors.lastname: Somer
authors.affiliation: Institute for Molecular Medicine Finland (M.M., A.P.), Neuroscience Center (M.M., A.L., A.-E.L.), and Research Programs Unit, Molecular Neurology (M.M., A.-K.A., A.L., A.-E.L.), University of Helsinki, Finland; Folkhälsan Institute of Genetics (M.M., A.-K.A., A.L., A.-E.L.), Helsinki, Finland; Division of Membrane Physiology (Y.F., M.F.), Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan; Department of Physiological Sciences (Y.F., M.F.), School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan; Medical and Clinical Genetics (A.-K.A.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Analytic and Translational Genetics Unit (A.P.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Program in Medical and Population Genetics (A.P.) and Stanley Center for Psychiatric Research (A.P.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Program in Genetics and Genomics (A.P.), Biological and Biomedical Sciences, Harvard Medical School, Boston, MA; Wellcome Trust Sanger Institute (A.P.), Wellcome Trust Genome Campus, Hinxton, United Kingdom; Psychiatric & Neurodevelopmental Genetics Unit (A.P.), Department of Psychiatry, and Department of Neurology (A.P.), Massachusetts General Hospital, Boston, MA; Department of Pediatric Neurology (H.P., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Radiology (L.V.), HUS Medical Imaging Center, Helsinki, Finland; and Family Federation of Finland (M.S.), Helsinki, Finland.
authors.forename: Masaki
authors.initials: M
authors.lastname: Fukata
authors.affiliation: Institute for Molecular Medicine Finland (M.M., A.P.), Neuroscience Center (M.M., A.L., A.-E.L.), and Research Programs Unit, Molecular Neurology (M.M., A.-K.A., A.L., A.-E.L.), University of Helsinki, Finland; Folkhälsan Institute of Genetics (M.M., A.-K.A., A.L., A.-E.L.), Helsinki, Finland; Division of Membrane Physiology (Y.F., M.F.), Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan; Department of Physiological Sciences (Y.F., M.F.), School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan; Medical and Clinical Genetics (A.-K.A.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Analytic and Translational Genetics Unit (A.P.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Program in Medical and Population Genetics (A.P.) and Stanley Center for Psychiatric Research (A.P.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Program in Genetics and Genomics (A.P.), Biological and Biomedical Sciences, Harvard Medical School, Boston, MA; Wellcome Trust Sanger Institute (A.P.), Wellcome Trust Genome Campus, Hinxton, United Kingdom; Psychiatric & Neurodevelopmental Genetics Unit (A.P.), Department of Psychiatry, and Department of Neurology (A.P.), Massachusetts General Hospital, Boston, MA; Department of Pediatric Neurology (H.P., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Radiology (L.V.), HUS Medical Imaging Center, Helsinki, Finland; and Family Federation of Finland (M.S.), Helsinki, Finland.
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki