Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome

Blood. 2016 Feb 25;127(8):997-1006. doi: 10.1182/blood-2015-09-671636.

Sandra Ammann ¹, Ansgar Schulz ², Ingeborg Krägeloh-Mann ³, Nele M G Dieckmann ⁴, Klaus Niethammer ⁵, Sebastian Fuchs ⁶, Katja Martina Eckl ⁷, Roswitha Plank ⁷, Roland Werner ⁸, Janine Altmüller ⁹, Holger Thiele ⁹, Peter Nürnberg ¹⁰, Julia Bank ⁶, Anne Strauss ², Horst von Bernuth ¹¹, Udo Zur Stadt ¹², Samantha Grieve ⁴, Gillian M Griffiths ⁴, Kai Lehmberg ¹³, Hans Christian Hennies ¹⁴, Stephan Ehl ¹⁵

Affiliations

1 Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany; Faculty of Biology, University Freiburg, Freiburg, Germany;
2 Department of Pediatrics, University Medical Center Ulm, Ulm, Germany;
3 Department of Pediatrics, University Medical Center Tübingen, Tübingen, Germany;
4 Cambridge Institute for Medical Research, Biomedical Campus, Cambridge, United Kingdom;
5 Department of Pediatrics, University Medical Center Esslingen, Esslingen, Germany;
6 Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany;
7 Cologne Center for Genomics, University of Cologne, Cologne, Germany; Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria;
8 Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria;
9 Cologne Center for Genomics, University of Cologne, Cologne, Germany;
10 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;
11 Department of Pediatrics, University Medical Center Charité Berlin, Berlin, Germany; Immunology, Berlin Laboratory, Charité Berlin Vivantes GmbH, Berlin, Germany;
12 Center for Diagnostics and.
13 Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and.
14 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;
15 Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, University Medical Center, Freiburg, Germany.

PMID: 26744459 DOI: 10.1182/blood-2015-09-671636

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.

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