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. 2022 Jan 19:12:786937.
doi: 10.3389/fphar.2021.786937. eCollection 2021.

Hermansky-Pudlak Syndrome: Identification of Novel Variants in the Genes HPS3, HPS5, and DTNBP1 (HPS-7)

Doris Boeckelmann  1 , Mira Wolter  1 , Katharina Neubauer  1 , Felix Sobotta  1 , Antonia Lenz  1 , Hannah Glonnegger  1 , Barbara Käsmann-Kellner  2 , Jasmin Mann  3 , Stephan Ehl  3 , Barbara Zieger  1
Affiliations

Hermansky-Pudlak Syndrome: Identification of Novel Variants in the Genes HPS3, HPS5, and DTNBP1 (HPS-7)

Doris Boeckelmann et al. Front Pharmacol. .

Abstract

Hermansky-Pudlak syndrome (HPS), a rare heterogeneous autosomal recessive disorder, is characterized by oculocutaneous albinism (OCA) and a bleeding diathesis due to a defect regarding melanosomes and platelet delta (δ)-granule secretion. Interestingly, patients with HPS type 2 (HPS-2) or HPS type 10 (HPS-10) present additionally with an immunological defect. We investigated three patients (IP1, IP2, and IP3) who suffer from a bleeding diathesis. Platelet aggregometry showed impaired platelet function and flow cytometry revealed a severely reduced platelet CD63 expression hinting to either a defect of platelet delta granule secretion or a decreased number of delta granules in these patients. However, only IP3 presents with an apparent OCA. We performed panel sequencing and identified a homozygous deletion of exon 6 in DTNBP1 for IP3. Western analysis confirmed the absence of the encoded protein dysbindin confirming the diagnosis of HPS-7. Interestingly, this patient reported additionally recurrent bacterial infections. Analysis of lymphocyte cytotoxicity showed a slightly reduced NK-degranulation previously documented in a more severe form in patients with HPS-2 or HPS-10. IP1 is carrier of two compound heterozygous variants in the HPS3 gene (c.65C > G and c.1193G > A). A homozygous variant in HPS5 (c.760G > T) was identified in IP2. The novel missense variants were classified as VUS (variant of uncertain significance) according to ACMG guidelines. For IP1 with the compound heterozygous variants in HPS3 a specialized ophthalmological examination showed ocular albinism. HPS3 and HPS5 encode subunits of the BLOC-2 complex and patients with HPS-3 or HPS-5 are known to present with variable/mild hypopigmentation.

Keywords: BLOC-1; BLOC-2; HPS-3; HPS-5; HPS-7; Hermansky-Pudlak syndrome (HPS).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Platelet granule secretion stimulated with thrombin (concentrations: 0, 0.05, 0.1, 0.2, 0.5, and 1.0 U/ml) for all three index patients using flow cytometry. Severely impaired δ-granule secretion indicated by reduced platelet CD63 expression in IP1 (A), IP2 (B), and IP3 (C) compared to the healthy controls/day control. Data are expressed as logarithmic arbitrary units (logAU) of anti-CD63-stained unstimulated and thrombin-stimulated platelets.
FIGURE 2
FIGURE 2
Results for patient IP3 (HPS-7). (A) Pedigree for IP3 (II.1). Her consanguine parents and her brother are already deceased, her brother presented with OCA and bleeding disorder. (B) Bioinformatics software SeqPilot CNV analysis indicates a homozygous deletion of exon 6 in DTNBP1. (C) Upper Panel: Schematic representation of the normally spliced mRNA (WT) and the aberrantly spliced mRNA of IP3. Lower Panel: cDNA sequencing of platelet derived DTNBP1 mRNA shows deletion of exon 6 and 7 in IP3. (D) Dysbindin expression in gel-filtrated platelets of the patient (IP3) and a healthy volunteer performed by Western analysis: Dysbindin is not expressed in patient’s platelets. GAPDH (37 kDa) was used as loading control (lower bands).
FIGURE 3
FIGURE 3
NK cell degranulation of IP3 is slightly reduced in response to K562. (A) Ex vivo degranulation of CD3− CD56+ NK cells from IP3 and a healthy day control (Co.) after incubation with medium (left panel) or NK-sensitive K562 target cells (middle panel) assessed by flow cytometric analysis of CD107a surface expression. Graphs in the right panel show ∆CD107a for the patient and healthy day controls (solid triangles) pooled from two independent experiments assessing fresh and activated (PHA/IL-2 pre-culture for 48 h) NK cell degranulation. ∆CD107a was calculated as the percentage of NK cells expressing CD107a after stimulation with K562 minus the percentage of NK cells expressing CD107a after incubation with medium. Blank circles represent historical controls (n = 28,17). The dashed line indicates the diagnostic cutoff below which NK cell degranulation is considered abnormal and equals the 10th percentile of a reference range. (B) Degranulation of CD3+ CD8+ CTL after incubation with medium (grey line) or anti-CD3/CD28 beads (black line).
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