Characterization of melanosomes and melanin in Japanese patients with Hermansky–Pudlak syndrome types 1, 4, 6, and 9

Okamura, Ken; Abe, Yuko; Araki, Yuta; Wakamatsu, Kazumasa; Seishima, Mariko; Umetsu, Takafumi; Kato, Atsushi; Kawaguchi, Masakazu; Hayashi, Masahiro; Hozumi, Yasukazu; Suzuki, Tamio

doi:10.1111/pcmr.12662

Cited by 28 publications

(51 citation statements)

References 44 publications

(71 reference statements)

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“… f Immunodeficiency was reported in two unrelated individuals with HPS‐9 (BLOC‐1 deficiency; Badolato et al, 2012; Okamura et al, 2018) and needs consideration in future BLOC‐1 deficient individuals.…”

Section: Introductionmentioning

confidence: 99%

“… i Both the Italian and Japanese subjects had a history of recurrent leucopenia and mild thrombocytopenia, causing immunodeficiency (Badolato et al, 2012; Okamura et al, 2018). The Japanese subject developed schizophrenia in her late forties, a phenotype also associated with DTNBP1 haplotypes.…”

Section: Introductionmentioning

confidence: 99%

“…A 17‐year‐old Italian female (Badolato et al, 2012) and a 4‐year‐old Pakistani female (Yousaf et al, 2016) were both homozygous for the same HPS9 nonsense variant: c.232C>T, p.Gln78* (NM_012388.3, transcript variant 2). A 52‐year‐old Japanese female was reported homozygous for c.285_286dupTC, p.H96Lfs*22 (NM_012388.3; Okamura et al, 2018; Table 9; Figure 7).…”

Section: Introductionmentioning

confidence: 99%

“…No pulmonary fibrosis or granulomatous colitis was reported in HPS‐9 subjects. However, the Italian (17‐year‐old female) and Japanese (52‐year‐old female) subjects both had mild thrombocytopenia and recurrent leukopenia, causing immunodeficiency (Badolato et al, 2012; Okamura et al, 2018). In addition, the Japanese subject developed schizophrenia in her late 40's, a phenotype previously associated with DTNBP1 haplotypes (Donohoe et al, 2008; Straub et al, 2002; Wang et al, 2017), however, this association appears controversial and needs further consideration (Ghiani & Dell'Angelica, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Recognition of these features may facilitate the diagnosis of affected individuals with HPS subtypes associated with BLOC‐1 defects. Several association studies have identified DTNBP1 variants as risk alleles for schizophrenia (Donohoe et al, 2008; Straub et al, 2002; Wang et al, 2017; Zuo et al, 2009) and one HPS‐9 subject was diagnosed with oculocutaneous albinism and developed schizophrenia in her 40's; she was only diagnosed with HPS‐9 at age 52 through a whole‐exome screen (Okamura et al, 2018). However, some reports have challenged brain‐associated functions of BLOC‐1 and/or a BLOC‐1 association with schizophrenia (Ghiani & Dell'Angelica, 2011), suggesting that this issue needs further consideration.…”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hermansky–Pudlak syndrome: Mutation update

et al. 2020

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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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Sex‐dimorphic effects of biogenesis of lysosome‐related organelles complex‐1 deficiency on mouse perinatal brain development

Lee

Larimore

Faúndez

et al. 2020

J of Neuroscience Research

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The function(s) of the Biogenesis of Lysosome‐related Organelles Complex‐1 (BLOC‐1) during brain development is to date largely unknown. Here, we investigated how its absence alters the trajectory of postnatal brain development using as model the pallid mouse. Most of the defects observed early postnatally in the mutant mice were more prominent in males than in females and in the hippocampus. Male mutant mice, but not females, had smaller brains as compared to sex‐matching wild types at postnatal day 1 (P1), this deficit was largely recovered by P14 and P45. An abnormal cytoarchitecture of the pyramidal cell layer of the hippocampus was observed in P1 pallid male, but not female, or juvenile mice (P45), along with severely decreased expression levels of the radial glial marker Glutamate‐Aspartate Transporter. Transcriptomic analyses showed that the overall response to the lack of functional BLOC‐1 was more pronounced in hippocampi at P1 than at P45 or in the cerebral cortex. These observations suggest that absence of BLOC‐1 renders males more susceptible to perinatal brain maldevelopment and although most abnormalities appear to have been resolved in juvenile animals, still permanent defects may be present, resulting in faulty neuronal circuits, and contribute to previously reported cognitive and behavioral phenotypes in adult BLOC‐1‐deficient mice.

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Characterization of melanosomes and melanin in Japanese patients with Hermansky–Pudlak syndrome types 1, 4, 6, and 9

Cited by 28 publications

References 44 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

Sex‐dimorphic effects of biogenesis of lysosome‐related organelles complex‐1 deficiency on mouse perinatal brain development

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