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

TY - JOUR

T1 - Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome

AU - Ammann, Sandra

AU - Schulz, Ansgar

AU - Krägeloh-Mann, Ingeborg

AU - Dieckmann, Nele M G

AU - Niethammer, Klaus

AU - Fuchs, Sebastian

AU - Eckl, Katja Martina

AU - Plank, Roswitha

AU - Werner, Roland

AU - Altmüller, Janine

AU - Thiele, Holger

AU - Nürnberg, Peter

AU - Bank, Julia

AU - Strauss, Anne

AU - von Bernuth, Horst

AU - Zur Stadt, Udo

AU - Grieve, Samantha

AU - Griffiths, Gillian M

AU - Lehmberg, Kai

AU - Hennies, Hans Christian

AU - Ehl, Stephan

N1 - © 2016 by The American Society of Hematology.

PY - 2016/2/25

Y1 - 2016/2/25

N2 - 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.

AB - 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.

U2 - 10.1182/blood-2015-09-671636

DO - 10.1182/blood-2015-09-671636

M3 - SCORING: Journal article

C2 - 26744459

VL - 127

SP - 997

EP - 1006

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 8

ER -