title: Zinc deficiency and low enterocyte zinc transporter expression in human patients with autism related mutations in SHANK3.
abstract: Phelan McDermid Syndrome (PMDS) is a genetic disorder characterized by features of Autism spectrum disorders. Similar to reports of Zn deficiency in autistic children, we have previously reported high incidence of Zn deficiency in PMDS. However, the underlying mechanisms are currently not well understood. Here, using inductively coupled plasma mass-spectrometry to measure the concentration of Zinc (Zn) and Copper (Cu) in hair samples from individuals with PMDS with 22q13.3 deletion including SHANK3 (SH3 and multiple ankyrin repeat domains 3), we report a high rate of abnormally low Zn/Cu ratios. To investigate possible underlying mechanisms, we generated enterocytes from PMDS patient-derived induced pluripotent stem cells and used Caco-2 cells with knockdown of SHANK3. We detected decreased expression of Zn uptake transporters ZIP2 and ZIP4 on mRNA and protein level correlating with SHANK3 expression levels, and found reduced levels of ZIP4 protein co-localizing with SHANK3 at the plasma membrane. We demonstrated that especially ZIP4 exists in a complex with SHANK3. Furthermore, we performed immunohistochemistry on gut sections from Shank3αβ knockout mice and confirmed a link between enterocytic SHANK3, ZIP2 and ZIP4. We conclude that apart from its well-known role in the CNS, SHANK3 might play a specific role in the GI tract.
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, 89081 Ulm, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Pfaender
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Dept., Neurocenter of Ulm University, 89081 Ulm, Germany.
authors.forename: Ann Katrin
authors.initials: AK
authors.lastname: Sauer
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Dept., Neurocenter of Ulm University, 89081 Ulm, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Hagmeyer
authors.affiliation: WG Molecular Analysis of Synaptopathies, Neurology Dept., Neurocenter of Ulm University, 89081 Ulm, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mangus
authors.affiliation: Institute of Neuroanatomy, Eberhard Karls University Tübingen, 72074 Tübingen, Germany.
authors.forename: Leonhard
authors.initials: L
authors.lastname: Linta
authors.affiliation: Institute of Neuroanatomy, Eberhard Karls University Tübingen, 72074 Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebau
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, 89081 Ulm, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Bockmann
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, 75015 Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, 75015 Paris, France.|University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, 75013 Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Huguet
authors.affiliation: Institut Pasteur, Human Genetics and Cognitive Functions Unit, 75015 Paris, France.|CNRS UMR 3571: Genes, Synapses and Cognition, Institut Pasteur, 75015 Paris, France.|University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, 75013 Paris, France.|FondaMental Foundation, 94010 Créteil, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bourgeron
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, 89081 Ulm, Germany.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.affiliation: Institute for Anatomy and Cell Biology, Ulm University, 89081 Ulm, Germany.|WG Molecular Analysis of Synaptopathies, Neurology Dept., Neurocenter of Ulm University, 89081 Ulm, Germany.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Grabrucker
mesh_terms: D000293:Adolescent; D018938:Caco-2 Cells; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics / Q000378:metabolism*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics / Q000378:metabolism; D003300:Copper; D020895:Enterocytes / Q000166:cytology / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006197:Hair / Q000737:chemistry; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D007223:Infant; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D015032:Zinc / Q000172:deficiency*
chemical_list: D027682:Cation Transport Proteins; D009419:Nerve Tissue Proteins; C492357:SHANK3 protein, human; C498424:SLC39A2 protein, human; C486791:SLC39A4 protein, human; D003300:Copper; D015032:Zinc