BLOC-2 subunit HPS6 deficiency affects the tubulation and secretion of von Willebrand factor from mouse endothelial cells

Abstract

Hermansky-Pudlak syndrome (HPS) is a recessive disorder with bleeding diathesis, which has been linked to platelet granule defects. Both platelet granules and endothelial Weibel-Palade bodies (WPBs) are members of lysosome-related organelles (LROs) whose formation is regulated by HPS protein associated complexes such as BLOC (biogenesis of lysosome-related organelles complex) -1, -2, -3, AP-3 (adaptor protein complex-3) and HOPS (homotypic fusion and protein sorting complex). Von Willebrand factor (VWF) is critical to hemostasis, which is stored in a highly-multimerized form as tubules in the WPBs. In this study, we found the defective, but varying, release of VWF into plasma after desmopressin (DDAVP) stimulation in HPS1 (BLOC-3 subunit), HPS6 (BLOC-2 subunit), and HPS9 (BLOC-1 subunit) deficient mice. In particular, VWF tubulation, a critical step in VWF maturation, was impaired in HPS6 deficient WPBs. This likely reflects a defective endothelium, contributing to the bleeding tendency in HPS mice or patients. The differentially defective regulated release of VWF in these HPS mouse models suggests the need for precise HPS genotyping before DDAVP administration to HPS patients.

Instability of BLOC‐2 and BLOC‐3 in Chinese patients with Hermansky‐Pudlak syndrome

“…Interestingly, we have identified only mutations in HPS genes encoding subunits of BLOC‐2 and BLOC‐3. As different HPS subtypes have been documented with variable phenotypes (Huizing et al, ) and variable responses to desmopressin (DDAVP) treatment on bleeding tendency (Cordova et al, ; Ma et al, ), the differential diagnosis of HPS subtypes will be important for their prognosis and interventions.…”

“…The precise genotyping of HPS subtypes is important for their intervention on bleeding diathesis. We have reported little or no response to the administration of desmopressin (DDAVP) in BLOC‐2 or BLOC‐3‐deficient mice (Ma et al, ). This alerts clinicians that alternative methods for the intervention of bleeding tendency in these HPS subtypes may be necessary.…”

The road to lysosome‐related organelles: Insights from Hermansky‐Pudlak syndrome and other rare diseases

“…BLOC‐2 mouse mutants have milder hypopigmentation phenotypes than BLOC‐1 mutant mice, and choroidal melanosomes are aberrantly clustered . Excessive bleeding in BLOC‐2‐deficient mice and HPS patients might be exacerbated by defects in the maturation and secretion of Weibel‐Palade bodies in endothelial cells . Upon endothelial cell damage, vWF is released from Weibel‐Palade bodies into long strings that capture platelets in the blood circulation; hence, the combined defects in endothelial vWF packaging and release and in platelet dense granule formation and release may impact bleeding susceptibility more in BLOC‐2 mutants than in other HPS variants.…”

Orchestration of Primary Hemostasis by Platelet and Endothelial Lysosome-Related Organelles

“…Endothelial cells that lack HPS6, a subunit of BLOC-2 complex associated with HPS type 6, have abnormal VWF tubulation and misshaped WPBs, potentially due to failed recruitment of proteins involved in acidification of WPB milieu. 74 Although the Golgi/TGN morphology sets the bar for WPB size and VWF tubulation affects the formation itself, more proteins at the site regulate WPB biogenesis like the AP-1 complex. 71 AP-1/clathrin is speculated to act as a corset, stabilizing the forming WPB during VWF-tubule assembly and preventing premature budding.…”

“…Such a case is that HPS, apart from defective δ-granule formation, has been shown to alter α-granule protein release (HPS2, HPS4, and HPS9), whereas, it has also been described to influence WPB morphology and maturation (HPS2 and HPS6). 74,80,89,90 Additionally, VWD, especially type 2 and 3, has been associated with impaired megakaryopoiesis and platelet dysfunction, implicating VWF/ GPIb-V-IX interactions in a novel role during platelet production. [95][96][97] Taken together, LRO disorders comprise a heterogeneous group that has a multisystemic phenotype.…”