Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milano, Milano, Italy; Foundation IRCCS Cà Granda Ospedale Maggiore Policlinico, Neurology Unit, Milano, Italy.
School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
Am J Hum Genet. 2023 Aug 3;110(8):1436-1443. doi: 10.1016/j.ajhg.2023.07.004. Epub 2023 Jul 24.
Hyperferritinemia is a frequent finding in several conditions, both genetic and acquired. We previously studied eleven healthy subjects from eight different families presenting with unexplained hyperferritinemia. Their findings suggested the existence of an autosomal-recessive disorder. We carried out whole-exome sequencing to detect the genetic cause of hyperferritinemia. Immunohistochemistry and flow cytometry assays were performed on liver biopsies and monocyte-macrophages to confirm the pathogenic role of the identified candidate variants. Through a combined approach of whole-exome sequencing and homozygosity mapping, we found bi-allelic STAB1 variants in ten subjects from seven families. STAB1 encodes the multifunctional scavenger receptor stabilin-1. Immunohistochemistry and flow cytometry analyses showed absent or markedly reduced stabilin-1 in liver samples, monocytes, and monocyte-derived macrophages. Our findings show a strong association between otherwise unexplained hyperferritinemia and bi-allelic STAB1 mutations suggesting the existence of another genetic cause of hyperferritinemia without iron overload and an unexpected function of stabilin-1 in ferritin metabolism.
高血铁黄素症是多种遗传和获得性疾病的常见表现。我们先前研究了 11 名来自 8 个不同家族的健康受试者，他们表现为不明原因的高血铁黄素症。研究结果提示存在常染色体隐性遗传疾病。我们进行了全外显子组测序以检测高血铁黄素症的遗传病因。通过对肝活检和单核细胞-巨噬细胞进行免疫组化和流式细胞术检测，证实了所鉴定候选变异的致病性作用。通过全外显子组测序和纯合子作图的联合方法，我们在来自 7 个家族的 10 名受试者中发现了 STAB1 的双等位基因突变。STAB1 编码多功能清道夫受体稳定素-1。免疫组化和流式细胞术分析显示，肝组织、单核细胞和单核细胞衍生的巨噬细胞中稳定素-1缺失或明显减少。我们的研究结果表明，原因不明的高血铁黄素症与 STAB1 的双等位基因突变之间存在很强的关联性，这提示存在另一种非铁过载的高血铁黄素症遗传病因，以及稳定素-1在铁蛋白代谢中意想不到的功能。
