Natural killer cell activity and dysfunction in Hermansky‐Pudlak syndrome

Gil-Krzewska, Aleksandra; Murakami, Yousuke; Peruzzi, Giovanna; O’Brien, Kevin; Merideth, Melissa A.; Cullinane, Andrew R.; Gahl, William A.; Coligan, John E.; Gochuico, Bernadette R.; Krzewski, Konrad

doi:10.1111/bjh.14390

Cited by 16 publications

(18 citation statements)

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“…Apart from the hypopigmentation and bleeding diathesis of HPS‐2, affected individuals are also at risk for developing interstitial lung disease and pulmonary fibrosis in childhood (Gochuico et al, 2012; Hengst et al, 2018); in addition, immunodeficiency associated with neutropenia is the most prevalent clinical feature (Fontana et al, 2006). The immunodeficiency, an impairment of cytotoxic activity, results from T‐lymphocyte and/or natural killer (NK) cell dysfunction and can present with variable features, from mild recurrent bacterial and viral infections to severe HLH (Gil‐Krzewska et al, 2017; Jessen et al, 2013). These features led to the discovery of the involvement of AP‐3 in different trafficking processes.…”

Section: Introductionmentioning

confidence: 99%

“…AP‐3 is involved in neutrophil formation (Badolato & Parolini, 2007; Massullo et al, 2005); AP‐3 deficient cells mislocalize the neutrophil granule proteins myeloperoxidase and elastase and the lysosomal membrane protein CD63 (de Boer et al, 2017; Di Pietro et al, 2006; Jung et al, 2006; Meng et al, 2010). The AP‐3 immunodeficiency also involves defective AP‐3‐mediated lytic granule exocytosis in NK‐cells and cytotoxic T cells (Clark et al, 2003; Fontana et al, 2006; Gil‐Krzewska et al, 2017; Jung et al, 2006). AP‐3 deficient dendritic cells showed impaired toll‐like receptor recruitment (Mantegazza et al, 2012; Sasai, Linehan, & Iwasaki, 2010), leading to defects in interferon production and antigen presentation in these cells from HPS‐2 subjects (Prandini et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Apart from the hypopigmentation and bleeding diathesis of HPS-2, affected individuals are also at risk for developing interstitial lung disease and pulmonary fibrosis in childhood (Gochuico et al, 2012;Hengst et al, 2018); in addition, immunodeficiency associated with neutropenia is the most prevalent clinical feature (Fontana et al, 2006). The AP-3 immunodeficiency also involves defective AP-3-mediated lytic granule exocytosis in NK-cells and cytotoxic T cells (Clark et al, 2003;Fontana et al, 2006;Gil-Krzewska et al, 2017;Jung et al, 2006).…”

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confidence: 99%

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Hermansky–Pudlak syndrome: Mutation update

et al. 2020

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Hermansky-Pudlak syndrome (HPS) is a group of 10 autosomal recessive multisystem disorders, each defined by the deficiency of a specific gene. HPS-associated genes encode components of four ubiquitously expressed protein complexes: Adaptor protein-3 (AP-3) and biogenesis of lysosome-related organelles complex-1 (BLOC-1) through -3. All individuals with HPS exhibit albinism and a bleeding diathesis; additional features occur depending on the defective protein complex. Pulmonary fibrosis is associated with AP-3 and BLOC-3 deficiency, immunodeficiency with AP-3 defects, and gastrointestinal symptoms are more prevalent and severe in BLOC-3 deficiency. Therefore, identification of the HPS subtype is valuable for prognosis, clinical management, and treatment options. The prevalence of HPS is estimated at 1-9 per 1,000,000. Here we summarize 264 reported and novel variants in 10 HPS genes and estimate that~333 Puerto Rican HPS subjects and~385 with other ethnicities are reported to date. We provide pathogenicity predictions for missense and splice site variants and list variants with high minor allele frequencies. Current cellular and clinical aspects of HPS are also summarized. This review can serve as a manifest for molecular diagnostics and genetic counseling aspects of HPS.

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confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hermansky–Pudlak syndrome: Mutation update

et al. 2020

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“…Granulomatous colitis resembling Crohn’s disease can affect a subpopulation of patients with HPS, and some disease manifestations are limited to specific HPS subtypes (Huizing, 2017). For example, pulmonary fibrosis develops in patients with HPS-1, -2, and -4, and immunodeficiency with natural killer cell dysfunction and neutropenia manifest in patients with HPS-2 (Huizing, 2017; Gochuico, 2012; Gil-Krzewska, 2017). …”

Section: Introductionmentioning

confidence: 99%

Severe bleeding with subclinical oculocutaneous albinism in a patient with a novel HPS6 missense variant

Han

O’Brien

Coon

et al. 2018

American J of Med Genetics Pt A

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Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder, manifests with oculocutaneous albinism and a bleeding diathesis. However, severity of disease can be variable and is typically related to the genetic subtype of HPS; HPS type 6 (HPS-6) is an uncommon subtype generally associated with mild disease. A Caucasian adult female presented with a history of severe bleeding; ophthalmologic examination indicated occult oculocutaneous albinism. The patient was diagnosed with a platelet storage pool disorder, and platelet whole mount electron microscopy demonstrated absent delta granules. Genome-wide SNP analysis showed regions of homozygosity that included the HPS1 and HPS6 genes. Full length HPS1 transcript was amplified by PCR of genomic DNA. Targeted next-generation sequencing identified a novel homozygous missense variant in HPS6 (c.383T>C; p.V128A); this was associated with significantly reduced HPS6 mRNA and protein expression in the patient’s fibroblasts compared to control cells. These findings highlight the variable severity of disease manifestations in patients with HPS, and illustrate that HPS can be diagnosed in patients with excessive bleeding and occult oculocutaneous albinism. Genetic analysis and platelet electron microscopy are useful diagnostic tests in evaluating patients with suspected HPS.

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“…In addition, certain manifestations of disease are limited to specific HPS types. For example, progressive and generally fatal pulmonary fibrosis develops in patients with HPS-1, -2, and -4, and HPS-2 patients manifest immunodeficiency and neutropenia responsive to granulocyte colony-stimulation factor [1, 5–9]. …”

Section: Introductionmentioning

confidence: 99%

Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS

Bryan

Tolman

Simon

et al. 2017

Molecular Genetics and Metabolism

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Purpose Hermansky-Pudlak syndrome (HPS) is a rare inherited disorder with ten reported genetic types; each type has defects in subunits of either Adaptor Protein-3 complex or Biogenesis of Lysosome-related Organelles Complex (BLOC)-1, -2, or -3. Very few patients with BLOC-1 deficiency (HPS-7, -8, and -9 types) have been diagnosed. We report results of comprehensive clinical testing and molecular analyses of primary fibroblasts from a new case of HPS-7. Results A 6-year old Paraguayan male presented with hypopigmentation, ocular albinism, nystagmus, reduced visual acuity, and easy bruising. He also experienced delayed motor and language development as a very young child; head and chest trauma resulted in intracranial hemorrhage with subsequent right hemiparesis and lung scarring. There was no clinical evidence of immunodeficiency or colitis. Whole mount transmission electron microscopy revealed absent platelet delta granules; platelet aggregation testing was abnormal. Exome sequencing revealed a homozygous nonsense mutation in the Dystrobrevin binding protein 1 (DTNBP1) gene [NM 032122.4: c.307C>T; p.Gln103*], previously reported in a Portuguese adult. The gene encodes the dysbindin subunit of BLOC-1. Dysbindin protein expression was negligible in our patient’s dermal fibroblasts, while his DTNBP1 mRNA level was similar to that of a normal control. Conclusions Comprehensive clinical evaluation of the first pediatric case reported with HPS-7 reveals oculocutaneous albinism and platelet storage pool deficiency; his phenotype is consistent with findings in other patients with BLOC-1 disorders. This patient’s markedly reduced Dysbindin protein expression in HPS-7 resulted from a mechanism other than nonsense mediated decay.

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Natural killer cell activity and dysfunction in Hermansky‐Pudlak syndrome

Cited by 16 publications

References 15 publications

Hermansky–Pudlak syndrome: Mutation update

Hermansky–Pudlak syndrome: Mutation update

Severe bleeding with subclinical oculocutaneous albinism in a patient with a novel HPS6 missense variant

Clinical and molecular phenotyping of a child with Hermansky-Pudlak syndrome-7, an uncommon genetic type of HPS

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