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


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


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Publication Date: 2016-01-07

Journal Title: Blood

Publisher: American Society of Hematology

Type: Article

Metadata: Show full item record

Citation: Ammann, S., Schulz, A., Krägeloh-Mann, I., Dieckmann, N. M. G., Niethammer, K., Fuchs, S., Eckl, K. M., et al. (2016). Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Blood

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Abstract: Genetic disorders affecting biogenesis and transport of lysosome-related organelles are heterogenous diseases frequently associated with albinism. We studied a patient with albinism, neutropenia and immunodeficiency, neurodevelopmental delay, generalized seizures and impaired hearing, but no mutation in genes so far associated with albinism and immunodeficiency. Whole exome sequencing identified a homozygous mutation in AP3D1, leading to destabilization of the adaptor protein 3 (AP-3) complex. AP-3 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 neurological phenotype with our patient and shows a platelet storage pool deficiency characteristic of HPS that was not studied in our patient due to lack of bleeding. HPS-2 caused by mutations in AP3B1A leads to a highly overlapping phenotype without the neurological symptoms. The AP-3 complex exists in a ubiquitous and a neuronal form. AP3D1 codes for the AP-3δ subunit of the complex, which is essential for both forms. In contrast, the AP-3β3A subunit, affected in HPS-2 patients, is substituted by AP-3β3B in the neuron-specific heterotetramer. AP-3δ deficiency thus causes a severe neurological disorder with immunodeficiency and albinism, which we propose to classify as HPS-10.

Sponsorship: This work was supported by grants EH 145/5-1 and SFB1160, TP1 (S.E.) and HE 3119/10-1 (H.C.H.) from the DFG, 01 EO 0803 (S.E.) from BMBF, by the K¨oln Fortune Program of the Faculty of Medicine, University of Cologne (H.C.H.), by grant 100140 from the Wellcome Trust, and by the National Institute for Health Research Biomedical Research Center (G.M.G.).

Identifiers:

This record's URL: http://dx.doi.org/10.1182/blood-2015-09-671636https://www.repository.cam.ac.uk/handle/1810/254704





Autor: Ammann, SandraSchulz, AnsgarKrägeloh-Mann, IngeborgDieckmann, Nele M. G.Niethammer, KlausFuchs, SebastianEckl, Katja MartinaPlank

Fuente: https://www.repository.cam.ac.uk/handle/1810/254704



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