title: Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome.
abstract: Genetic disorders affecting biogenesis and transport of lysosome-related organelles are heterogeneous diseases frequently associated with albinism. We studied a patient with albinism, neutropenia, immunodeficiency, neurodevelopmental delay, generalized seizures, and impaired hearing but with no mutation in genes so far associated with albinism and immunodeficiency. Whole exome sequencing identified a homozygous mutation in AP3D1 that leads to destabilization of the adaptor protein 3 (AP3) complex. AP3 complex formation and the degranulation defect in patient T cells were restored by retroviral reconstitution. A previously described hypopigmented mouse mutant with an Ap3d1 null mutation (mocha strain) shares the neurologic phenotype with our patient and shows a platelet storage pool deficiency characteristic of Hermansky-Pudlak syndrome (HPS) that was not studied in our patient because of a lack of bleeding. HPS2 caused by mutations in AP3B1A leads to a highly overlapping phenotype without the neurologic symptoms. The AP3 complex exists in a ubiquitous and a neuronal form. AP3D1 codes for the AP3δ subunit of the complex, which is essential for both forms. In contrast, the AP3β3A subunit, affected in HPS2 patients, is substituted by AP3β3B in the neuron-specific heterotetramer. AP3δ deficiency thus causes a severe neurologic disorder with immunodeficiency and albinism that we propose to classify as HPS10.
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany; Faculty of Biology, University Freiburg, Freiburg, Germany;
authors.forename: Sandra
authors.initials: S
authors.lastname: Ammann
authors.affiliation: Department of Pediatrics, University Medical Center Ulm, Ulm, Germany;
authors.forename: Ansgar
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Department of Pediatrics, University Medical Center Tübingen, Tübingen, Germany;
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Krägeloh-Mann
authors.affiliation: Cambridge Institute for Medical Research, Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Nele M G
authors.initials: NM
authors.lastname: Dieckmann
authors.affiliation: Department of Pediatrics, University Medical Center Esslingen, Esslingen, Germany;
authors.forename: Klaus
authors.initials: K
authors.lastname: Niethammer
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Fuchs
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany; Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria;
authors.forename: Katja Martina
authors.initials: KM
authors.lastname: Eckl
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany; Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria;
authors.forename: Roswitha
authors.initials: R
authors.lastname: Plank
authors.affiliation: Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria;
authors.forename: Roland
authors.initials: R
authors.lastname: Werner
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany;
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany;
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany;
authors.forename: Julia
authors.initials: J
authors.lastname: Bank
authors.affiliation: Department of Pediatrics, University Medical Center Ulm, Ulm, Germany;
authors.forename: Anne
authors.initials: A
authors.lastname: Strauss
authors.affiliation: Department of Pediatrics, University Medical Center Charité Berlin, Berlin, Germany; Immunology, Berlin Laboratory, Charité Berlin Vivantes GmbH, Berlin, Germany;
authors.forename: Horst
authors.initials: H
authors.lastname: von Bernuth
authors.affiliation: Center for Diagnostics and.
authors.forename: Udo
authors.initials: U
authors.lastname: Zur Stadt
authors.affiliation: Cambridge Institute for Medical Research, Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Samantha
authors.initials: S
authors.lastname: Grieve
authors.affiliation: Cambridge Institute for Medical Research, Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Griffiths
authors.affiliation: Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and.
authors.forename: Kai
authors.initials: K
authors.lastname: Lehmberg
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany; Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Hennies
authors.affiliation: Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, Germany.
authors.forename: Stephan
authors.identifier: http://orcid.org/0000-0002-9265-2721
authors.initials: S
authors.lastname: Ehl
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000235:genetics*; D033981:Adaptor Protein Complex delta Subunits / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D005455:Fluorescent Antibody Technique; D022861:Hermanski-Pudlak Syndrome / Q000145:classification* / Q000235:genetics*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D009154:Mutation; D012640:Seizures / Q000235:genetics*; D014162:Transfection
chemical_list: C491904:AP3D1 protein, human; D033963:Adaptor Protein Complex 3; D033981:Adaptor Protein Complex delta Subunits