Study of Albinism in Relation to Hermanský-Pudlák Syndrome

Hermansky, F; Cieslar, P; Matousová, O; Smetana, Keaton S.

doi:10.1055/s-0039-1689206

Cited by 4 publications

(3 citation statements)

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“…After mixing with scintillation cocktail, radioactivity was measured. Acid sphingomyelinase de¢ciency 209 Table 3 a Published as NiemannÀPick type C (Elleder et al 1975) and subsequently in biochemically veri¢ed form (Elleder et al 1980) b Two sisters died with similar symptomatology c For further details see case 2 in (Elleder and Cihula 1983) d Published as 'sea-blue histiocyte syndrome', case 1 in Hermansky et al (1971). Revision of the autopsy protocol and additional histochemical examination showed ¢ndings compatible with ASM de¢ciency (Elleder 1989).…”

Section: Armsmentioning

confidence: 99%

Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty‐five Czech and Slovak patients. A multi‐approach study

Pavlu-Pereira¹,

Asfaw²,

Poupčtová³

et al. 2005

J of Inher Metab Disea

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A multi-approach study in a series of 25 Czech and Slovak patients with acid sphingomyelinase deficiency revealed a broad phenotypic variability within Niemann-Pick disease types A and B. The clinical manifestation of only 9 patients fulfilled the historical classification: 5 with the rapidly progressive neurovisceral infantile type A and 4 with a slowly progressive visceral type B. Sixteen patients (64%) represented a hitherto scarcely documented 'intermediate type' (IT). Twelve patients showed a protracted neurovisceral course with overt or mild neurological symptoms, three a rapidly progressing fatal visceral affection with rudimentary neurological lesion. One patient died early from a severe visceral disease. The genotype in our patients was represented by 4 frameshift and 14 missense mutations. Six were novel (G166R, R228H, A241V, D251E, D278A, A595fsX601). The Q292K mutation (homoallelic, heteroallelic) was strongly associated with a protracted neurovisceral phenotype (10 of 12 cases). The sphingomyelin loading test in living fibroblasts resulted in total degradation from less than 2% in classical type A to 70-80% in classical type B. In the IT group it ranged from 5% to 49% in a 24 h chase. The liver storage showed three patterns: diffuse, zonal (centrolobular), and discrete submicroscopic. Our series showed a notable variability in both the neurological and visceral lesions as well as in their proportionality and synchrony, and demonstrates a continuum between the historical 'A' and 'B' phenotypes of ASM deficiency. This points to a broad phenotypic potential of ASM deficiency, suggesting the existence of still unknown factors independently controlling the storage level in the visceral and neuronal compartments. This report highlights the important position of the IT in the ASM deficiency phenotype classification. We define IT as a cluster of variants combining clinical features of both the classical types. The protracted neuronopathic variant with overt, borderline or subclinical neurology prevails and is important in view of future enzyme replacement therapy. It appears more common in central Europe. The visceral, rapidly progressing early fatal type has been recognized rarely so far.

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Section: Armsmentioning

confidence: 99%

Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty‐five Czech and Slovak patients. A multi‐approach study

Pavlu-Pereira¹,

Asfaw²,

Poupčtová³

et al. 2005

J of Inher Metab Disea

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“…Mutations in β3A-subunit of AP3 (encoded by AP3B1 ) cause instability of the protein, which leads to the loss of the entire AP3 complex ( 79 , 80 ). As mentioned previously, HSP2 patients commonly present immunodeficiency, oculocutaneous albinism, and excessive bleeding, implicating impaired functions of cells with secretory lysosomes ( 81 ). Because AP3 is ubiquitously expressed, AP3-mediated protein sorting seems to be especially critical in the biogenesis of secretory lysosomes and/or in the sorting of secretory lysosome-specific proteins.…”

Section: Biogenesis Of Lytic Granulesmentioning

confidence: 89%

Locked and Loaded: Mechanisms Regulating Natural Killer Cell Lytic Granule Biogenesis and Release

2022

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NK cell-mediated cytotoxicity is a critical element of our immune system required for protection from microbial infections and cancer. NK cells bind to and eliminate infected or cancerous cells via direct secretion of cytotoxic molecules toward the bound target cells. In this review, we summarize the current understanding of the molecular regulations of NK cell cytotoxicity, focusing on lytic granule development and degranulation processes. NK cells synthesize apoptosis-inducing proteins and package them into specialized organelles known as lytic granules (LGs). Upon activation of NK cells, LGs converge with the microtubule organizing center through dynein-dependent movement along microtubules, ultimately polarizing to the cytotoxic synapse where they subsequently fuse with the NK plasma membrane. From LGs biogenesis to degranulation, NK cells utilize several strategies to protect themselves from their own cytotoxic molecules. Additionally, molecular pathways that enable NK cells to perform serial killing are beginning to be elucidated. These advances in the understanding of the molecular pathways behind NK cell cytotoxicity will be important to not only improve current NK cell-based anti-cancer therapies but also to support the discovery of additional therapeutic opportunities.

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“…Hermansky–Pudlak syndrome is an autosomal recessive disease clinically characterized by oculocutaneous albinism and excessive bleeding (67, 68). Among the currently identified nine different types of HPS, Hermansky–Pudlak syndrome type 2 (HPS2) is the only type known to cause immunodeficiency in addition to other clinical symptoms (67, 69, 70).…”

Section: Biogenesis Of Lytic Granules and Their Maturationmentioning

confidence: 99%

Human Immunodeficiency Syndromes Affecting Human Natural Killer Cell Cytolytic Activity

Ham

Billadeau

2014

Front. Immunol.

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Natural killer (NK) cells are lymphocytes of the innate immune system that secrete cytokines upon activation and mediate the killing of tumor cells and virus-infected cells, especially those that escape the adaptive T cell response caused by the down regulation of MHC-I. The induction of cytotoxicity requires that NK cells contact target cells through adhesion receptors, and initiate activation signaling leading to increased adhesion and accumulation of F-actin at the NK cell cytotoxic synapse. Concurrently, lytic granules undergo minus-end directed movement and accumulate at the microtubule-organizing center through the interaction with microtubule motor proteins, followed by polarization of the lethal cargo toward the target cell. Ultimately, myosin-dependent movement of the lytic granules toward the NK cell plasma membrane through F-actin channels, along with soluble N-ethylmaleimide-sensitive factor attachment protein receptor-dependent fusion, promotes the release of the lytic granule contents into the cleft between the NK cell and target cell resulting in target cell killing. Herein, we will discuss several disease-causing mutations in primary immunodeficiency syndromes and how they impact NK cell-mediated killing by disrupting distinct steps of this tightly regulated process.

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Study of Albinism in Relation to Hermanský-Pudlák Syndrome

Cited by 4 publications

References 0 publications

Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty‐five Czech and Slovak patients. A multi‐approach study

Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty‐five Czech and Slovak patients. A multi‐approach study

Locked and Loaded: Mechanisms Regulating Natural Killer Cell Lytic Granule Biogenesis and Release

Human Immunodeficiency Syndromes Affecting Human Natural Killer Cell Cytolytic Activity

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