Rare Diseases, Genetics and Metabolism, INSERM U1211, University of Bordeaux, Bordeaux, France.
Molecular Genetics Laboratory, Bordeaux University Hospital, Bordeaux, France.
Genet Med. 2020 Oct;22(10):1613-1622. doi: 10.1038/s41436-020-0867-5. Epub 2020 Jun 22.
Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, excessive bleeding, and often additional symptoms. Variants in ten different genes have been involved in HPS. However, some patients lack variants in these genes. We aimed to identify new genes involved in nonsyndromic or syndromic forms of albinism.
Two hundred thirty albinism patients lacking a molecular diagnosis of albinism were screened for pathogenic variants in candidate genes with known links to pigmentation or HPS pathophysiology.
We identified two unrelated patients with distinct homozygous variants of the BLOC1S5 gene. Patients had mild oculocutaneous albinism, moderate bleeding diathesis, platelet aggregation deficit, and a dramatically decreased number of platelet dense granules, all signs compatible with HPS. Functional tests performed on platelets of one patient displayed an absence of the obligate multisubunit complex BLOC-1, showing that the variant disrupts BLOC1S5 function and impairs BLOC-1 assembly. Expression of the patient-derived BLOC1S5 deletion in nonpigmented murine Bloc1s5 melan-mu melanocytes failed to rescue pigmentation, the assembly of a functional BLOC-1 complex, and melanosome cargo trafficking, unlike the wild-type allele.
Mutation of BLOC1S5 is disease-causing, and we propose that BLOC1S5 is the gene for a new form of Hermansky-Pudlak syndrome, HPS-11.
Hermansky-Pudlak 综合征（HPS）的特征是眼皮肤白化病、过度出血，并且通常还有其他附加症状。十种不同基因的变异与 HPS 有关。然而，一些患者缺乏这些基因的变异。我们旨在鉴定新的与非综合征或综合征形式的白化病有关的基因。
我们筛选了 230 名缺乏白化病分子诊断的白化病患者，以检测候选基因中的致病性变异，这些候选基因与色素沉着或 HPS 病理生理学有已知的联系。
我们鉴定了两名无关联的患者，他们携带 BLOC1S5 基因的不同纯合变异。患者有轻度眼皮肤白化病、中度出血倾向、血小板聚集缺陷和血小板致密颗粒数量显著减少，所有这些迹象都与 HPS 相符。对一名患者的血小板进行的功能测试显示，必需的多亚基复合物 BLOC-1 缺失，表明该变异破坏了 BLOC1S5 的功能并阻碍了 BLOC-1 的组装。与野生型等位基因不同，患者来源的 BLOC1S5 缺失在非色素黑素瘤小鼠 Bloc1s5 melan-mu 黑素细胞中的表达未能挽救色素沉着、功能性 BLOC-1 复合物的组装和黑素体货物运输。
BLOC1S5 的突变是致病的，我们提出 BLOC1S5 是一种新的 Hermansky-Pudlak 综合征（HPS-11）的致病基因。
