Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome.
Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome.
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DOI：
10.1182/blood-2015-09-671636
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发表时间：
2016-02-25
期刊：
影响因子：
20.3
通讯作者：
Ehl S
中科院分区：
文献类型：
--
作者：
Ammann S;Schulz A;Krägeloh-Mann I;Dieckmann NM;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
影响溶酶体相关细胞器的生物发生和运输的遗传性疾病是常与白化病相关的异质性疾病。我们研究了一名患有白化病、中性粒细胞减少症和免疫缺陷、神经发育迟缓、全身性癫痫发作和听力受损的患者，但迄今为止没有与白化病和免疫缺陷相关的基因突变。全外显子组测序鉴定了AP 3D 1中的纯合突变，导致接头蛋白3（AP-3）复合物的不稳定。通过逆转录病毒重建恢复了患者T细胞中AP-3复合物的形成和脱粒缺陷。先前描述的色素减退的小鼠突变与Ap 3d 1无效突变（摩卡株）共享的神经系统表型与我们的病人，并显示出血小板储存池缺乏的特点HPS，没有研究在我们的病人，由于缺乏出血。由AP 3B 1A突变引起的HPS-2导致高度重叠的表型，而没有神经症状。AP-3复合物以普遍存在的神经元形式存在。AP 3D 1编码复合物的AP-3δ亚基，这是两种形式所必需的。相反，在HPS-2患者中受影响的AP-3β3A亚基在神经元特异性异源四聚体中被AP-3β3B取代。因此，AP-3δ缺陷导致严重的神经系统疾病，伴有免疫缺陷和白化病，我们建议将其归类为HPS-10。
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.
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影响因子：
5.9
作者：
GRISCELLI, C;DURANDY, A;PRUNIERAS, M
通讯作者：
PRUNIERAS, M
影响因子：
20.3
作者：
Bryceson, Yenan T.;Pende, Daniela;Ehl, Stephan
通讯作者：
Ehl, Stephan
影响因子：
16
作者：
Dell'Angelica, EC;Shotelersuk, V;Bonifacino, JS
通讯作者：
Bonifacino, JS
影响因子：
7.5
作者：
Dell'Angelica, Esteban C.
通讯作者：
Dell'Angelica, Esteban C.
影响因子：
30.5
作者：
Clark, RH;Stinchcombe, JC;Griffiths, GM
通讯作者：
Griffiths, GM