Universität zu Köln

Ammann, Sandra ORCID: 0000-0003-0385-1890, Schulz, Ansgar, Kraegeloh-Mann, Ingeborg, Dieckmann, Nele M. G., Niethammer, Klaus, Fuchs, Sebastian ORCID: 0000-0001-9191-7970, Eckl, Katja Martina, Plank, Roswitha, Werner, Roland, Altmueller, Janine, Thiele, Holger, Nuernberg, Peter, Bank, Julia, Strauss, Anne, von Bernuth, Horst, zur Stadt, Udo, Grieve, Samantha, Griffiths, Gillian M., Lehmberg, Kai, Hennies, Hans Christian and Ehl, Stephan (2016). Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood, 127 (8). S. 997 - 1007. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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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 AP3d subunit of the complex, which is essential for both forms. In contrast, the AP3b3A subunit, affected in HPS2 patients, is substituted by AP3b3B in the neuron-specific heterotetramer. AP3d deficiency thus causes a severe neurologic disorder with immunodeficiency and albinism that we propose to classify as HPS10.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ammann, Sandra UNSPECIFIED orcid.org/0000-0003-0385-1890 UNSPECIFIED Schulz, Ansgar UNSPECIFIED UNSPECIFIED UNSPECIFIED Kraegeloh-Mann, Ingeborg UNSPECIFIED UNSPECIFIED UNSPECIFIED Dieckmann, Nele M. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Niethammer, Klaus UNSPECIFIED UNSPECIFIED UNSPECIFIED Fuchs, Sebastian UNSPECIFIED orcid.org/0000-0001-9191-7970 UNSPECIFIED Eckl, Katja Martina UNSPECIFIED UNSPECIFIED UNSPECIFIED Plank, Roswitha UNSPECIFIED UNSPECIFIED UNSPECIFIED Werner, Roland UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Bank, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Strauss, Anne UNSPECIFIED UNSPECIFIED UNSPECIFIED von Bernuth, Horst UNSPECIFIED UNSPECIFIED UNSPECIFIED zur Stadt, Udo UNSPECIFIED UNSPECIFIED UNSPECIFIED Grieve, Samantha UNSPECIFIED UNSPECIFIED UNSPECIFIED Griffiths, Gillian M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lehmberg, Kai UNSPECIFIED UNSPECIFIED UNSPECIFIED Hennies, Hans Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Ehl, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-284251
DOI:	10.1182/blood-2015-09-671636
Journal or Publication Title:	Blood
Volume:	127
Number:	8
Page Range:	S. 997 - 1007
Date:	2016
Publisher:	AMER SOC HEMATOLOGY
Place of Publication:	WASHINGTON
ISSN:	1528-0020
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language STORAGE POOL DEFICIENCY; ADAPTER PROTEIN-3; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; AP-3; COMPLEX; CELLS; MECHANISMS; ALBINISM; TRANSPORT; IMMUNITY Multiple languages Hematology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/28425