The first human case with heme oxygenase-1 deficiency : investigation of vascular endothelial injuries and an experimental study for gene therapy

报告第一例血红素加氧酶-1(HO-1)缺乏症。患者是一名6岁男孩，完全缺乏HO-1，母亲等位基因外显子2缺失，父亲等位基因外显子3双碱基缺失。进一步的分析揭示了这种情况下由Alu-Alu重组介导的基因组外显子缺失的结构证据。与最近描述的HO-1基因敲除小鼠相似，男孩表现出严重的生长迟缓、贫血、肾脏和肝脏组织中的铁沉积，以及对应激相关损伤的脆弱性。连续三次活检标本均可见肾小球毛细血管壁厚的系膜改变。电子显微镜检查显示广泛的内皮细胞脱离和内皮下的不明物质沉积。值得注意的是，随着肾小管扩张和/或萎缩、间质纤维化和炎细胞浸润，肾小管间质损伤逐渐加重。此外，男孩的单核细胞形态异常，其表面分子CD11b、CD14、CD16和CD36显著减少，导致单核细胞吞噬功能明显受损。血红素加氧酶催化血红素转化为一氧化碳和胆绿素，在氧化损伤中起着重要的抗炎作用。这两个已知的亚型在表达模式上有所不同，HO-2在脑和睾丸中结构性表达，HO-1在低水平普遍表达，尽管在不同的应激条件下会迅速诱导表达。目前这项工作的重要性可能不在于它是第一个描述的人类HO-1缺乏症病例，而在于它为这种重要酶的正常功能提供了线索。

The first-described case of heme oxygenase-1 (HO-1) deficiency is presented. The patient, a 6-year-old boy, completely lacks HO-1, having a deletion of exon 2 of the maternal allele and a two-base-pair deletion in exon 3 of the paternal allele of the gene. Further analysis revealed structural evidence of genomic exon-deletion mediated by Alu-Alu recombination in this case. Similar to recently described HO-1 knockout mice, the boy exhibits severe growth retardation, anemia, iron deposition in renal and hepatic tissue, and vulnerability to stress-related injury. Mesangial change in glomerular capillary-wall thickness was shown in the three consecutive biopsy specimens. Electron microscopic examination showed widespread endothelial detachment and subendothelial deposits of an unidentifiable material. It was striking that tubulointerstitial injury, with tubular dilatation and/or atrophy, interstitial fibrosis, and inflammatory cell infiltration, advanced progressively. In addition, the boy exhibited morphological abnormality of monocytes and significant reduction of their surface molecules including CD11b, CD14, CD16 and CD36, resulting in a markedly impaired phagocytosis of monocytes.Heme oxygenase, which catalyzes the conversion of heme into carbon monoxide and biliverdin, plays an important anti-inflammatory role in oxidative injury. The two known isoforms differ in their expression pattern, with HO-2 constitutively expressed in brain and testis, and HO-1 expressed ubiquitously at low levels, although it is rapidly induced following various stresses. The importance of the current work may lie less in its being the first described case of human HO-1 deficiency than in the clues it provides to the normal functions of this important enzyme.