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

Abstract

Hermansky‐Pudlak syndrome (HPS) is a rare recessive disorder characterized by oculocutaneous albinism (OCA) or ocular albinism (OA), bleeding tendency, and other symptoms due to multiple defects in tissue‐specific lysosome‐related organelles. Ten HPS subtypes have been characterized with mutations in HPS1 to HPS10, which encode the subunits of BLOC‐1, ‐2, ‐3, and AP‐3. Using next‐generation sequencing (NGS), we have screened 100 hypopigmentation genes in OCA or OA patients and identified four HPS‐1, one HPS‐3, one HPS‐4, one HPS‐5, and three HPS‐6. The HPS‐4 case is the first report in the Chinese population. Among these 20 mutational alleles, 16 were previously unreported alleles (6 in HPS1, 1 in HPS3, 2 in HPS4, 2 in HPS5, and 5 in HPS6). BLOC‐2 and BLOC‐3 were destabilized due to the mutation of these HPS genes which are so far the only reported causative genes in Chinese HPS patients, in which HPS‐1 and HPS‐6 are the most common subtypes. The mutational spectrum of Chinese HPS is population specific.

Donskoy cats as a new model of oculocutaneous albinism with the identification of a splice‐site variant in Hermansky–Pudlak Syndrome 5 gene

“…Altogether, reduced skin and iris pigmentation, red-eye effect and reduced retinal pigment on fundoscopic examination, and the apparent absence of bleeding tendency are consistent with a mild OCA in pink-eye cats. This phenotype is also consistent with a HPS type 5, as variants in HPS5 in human patients are associated with a spectrum of phenotypes combining OCA or OA with or without visual impairment, bleeding diathesis and colitis (Botero et al, 2018;Michaud et al, 2017;Wei et al, 2019).…”

Hermansky–Pudlak syndrome: Mutation update

“…Candidate genes for new HPS subtypes may include genes affected in mouse models of HPS that do not yet have a human counterpart (Table 1) | 569 (Lasseaux et al, 2018). A similar study of 21 Arabian individuals with ocular hypopigmentation identified 10 HPS subjects (Khan et al, 2016), a study of 46 Japanese cases with (OCA-1 and HPS-1 negative) albinism identified nine HPS subjects (Okamura et al, 2019), and a study of Chinese hypopigmentation cases identified 10 HPS subjects (Wei et al, 2019). Similarly, targeted sequencing of a cohort of 159 cases with bleeding, thrombotic, and platelet disorders identified six HPS individuals (Simeoni et al, 2016).…”

“…Immunoblotting of cultured skin fibroblast or platelet‐rich plasma extracts has also proven helpful to determine or validate the HPS subtype. HPS mouse and human studies have shown that a defect in one HPS protein leads to destabilization of the entire protein complex, that is AP‐3, BLOC‐1, ‐2, ‐3 (Ammann et al, 2016; Dell'Angelica et al, 1999; Huizing et al, 2002; Li et al, 2003; Wei et al, 2019). Therefore, the use of immunoblotting with an antibody against one subunit of the complex (AP‐3 and BLOC‐1,‐2,‐3) allows determination of which complex is defective in unclassified HPS subjects, reducing subsequent sequencing of genes encoding the corresponding subunits (Carmona‐Rivera, Hess et al, 2011; Nazarian et al, 2008; Wei et al, 2019).…”

HPS1 Regulates the Maturation of Large Dense Core Vesicles and Lysozyme Secretion in Paneth Cells

“…Patients recruited in this study were diagnosed with HPS-1 at Beijing Tongren Hospital from 2013 to 2018. Diagnosis of HPS was based on clinical manifestations, absence of platelet dense granules under electron microscopy, loss of platelet HPS1 or HPS4 protein by Western blotting ( 18 ). Mutations of the HPS1 gene confirmed the diagnosis of HPS-1 by next-generation sequencing ( 22 ).…”

“…HPS-1 is the predominant subtype accounting for 47.5% of reported HPS cases in the Chinese population (18). HPS1 and HPS4 proteins are found in the BLOC-3 complex.…”