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

Sandra Ammann, Ansgar Schulz, Ingeborg Krägeloh-Mann, Nele M G Dieckmann, Klaus Niethammer, Sebastian Fuchs, Katja Martina Eckl, Roswitha Plank, Roland Werner, Janine Altmüller, Holger Thiele, Peter Nürnberg, Julia Bank, Anne Strauss, Horst Von Bernuth, Udo Zur Stadt, Samantha Grieve, Gillian M. Griffiths, Kai Lehmberg, Hans Christian Hennies & 1 others Stephan Ehl

Research output: Contribution to journalArticle

52 Citations (Scopus)

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 neuronspecific heterotetramer. AP3δ deficiency thus causes a severe neurologic disorder with immunodeficiency and albinism that we propose to classify as HPS10.

Original languageEnglish
Pages (from-to)997-1006
Number of pages10
JournalBlood
Volume127
Issue number8
Early online date7 Jan 2016
DOIs
Publication statusPublished - 25 Feb 2016
Externally publishedYes

Fingerprint

Adaptor Protein Complex 3
Hermanski-Pudlak Syndrome
Albinism
Seizures
Mutation
T-cells
Adaptor Protein Complex Subunits
Audition
Platelets
Platelet Storage Pool Deficiency
Exome
Proteins
Phenotype
Genes
Protein Deficiency
Inborn Genetic Diseases
Defects
Neurologic Manifestations
Lysosomes
Neutropenia

Cite this

Ammann, S., Schulz, A., Krägeloh-Mann, I., Dieckmann, N. M. G., Niethammer, K., Fuchs, S., ... Ehl, S. (2016). Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood, 127(8), 997-1006. https://doi.org/10.1182/blood-2015-09-671636
Ammann, Sandra ; Schulz, Ansgar ; Krägeloh-Mann, Ingeborg ; Dieckmann, Nele M G ; Niethammer, Klaus ; Fuchs, Sebastian ; Eckl, Katja Martina ; Plank, Roswitha ; Werner, Roland ; Altmüller, Janine ; Thiele, Holger ; Nürnberg, Peter ; Bank, Julia ; Strauss, Anne ; Von Bernuth, Horst ; Zur Stadt, Udo ; Grieve, Samantha ; Griffiths, Gillian M. ; Lehmberg, Kai ; Hennies, Hans Christian ; Ehl, Stephan. / Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. In: Blood. 2016 ; Vol. 127, No. 8. pp. 997-1006.
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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 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 neuronspecific heterotetramer. AP3δ deficiency thus causes a severe neurologic disorder with immunodeficiency and albinism that we propose to classify as HPS10.",
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Ammann, S, Schulz, A, Krägeloh-Mann, I, Dieckmann, NMG, Niethammer, K, Fuchs, S, Eckl, KM, Plank, R, Werner, R, Altmüller, J, Thiele, H, Nürnberg, P, Bank, J, Strauss, A, Von Bernuth, H, Zur Stadt, U, Grieve, S, Griffiths, GM, Lehmberg, K, Hennies, HC & Ehl, S 2016, 'Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome', Blood, vol. 127, no. 8, pp. 997-1006. https://doi.org/10.1182/blood-2015-09-671636

Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. / Ammann, Sandra; Schulz, Ansgar; Krägeloh-Mann, Ingeborg; Dieckmann, Nele M G; Niethammer, Klaus; Fuchs, Sebastian; Eckl, Katja Martina; Plank, Roswitha; Werner, Roland; Altmüller, Janine; Thiele, Holger; Nürnberg, Peter; Bank, Julia; Strauss, Anne; Von Bernuth, Horst; Zur Stadt, Udo; Grieve, Samantha; Griffiths, Gillian M.; Lehmberg, Kai; Hennies, Hans Christian; Ehl, Stephan.

In: Blood, Vol. 127, No. 8, 25.02.2016, p. 997-1006.

Research output: Contribution to journalArticle

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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 - No full text in Eprints. HN 07/11/2017

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 neuronspecific 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 neuronspecific heterotetramer. AP3δ deficiency thus causes a severe neurologic disorder with immunodeficiency and albinism that we propose to classify as HPS10.

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Ammann S, Schulz A, Krägeloh-Mann I, Dieckmann NMG, Niethammer K, Fuchs S et al. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood. 2016 Feb 25;127(8):997-1006. https://doi.org/10.1182/blood-2015-09-671636