Genetics, clinical and pathological features of glomerulonephrites associated with mutations of nonmuscle myosin IIA (Fechtner syndrome)
Genetics, clinical and pathological features of glomerulonephrites associated with mutations of nonmuscle myosin IIA (Fechtner syndrome)
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DOI：
10.1053/ajkd.2003.50028
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发表时间：
2003-01-01
影响因子：
13.2
通讯作者：
Balduini, CL
中科院分区：
文献类型：
--
作者：
Ghiggeri, GM;Caridi, G;Balduini, CL
背景资料：Fechtner综合征（FTNS），也称为Alport样综合征，是一种罕见的遗传性疾病，其特征为进行性肾炎、巨血小板减少症、Dohle样白细胞夹杂物、耳聋和白内障。虽然最近研究表明FTNS是由非肌肉肌球蛋白IIA重链（NMMHC-IIA）基因MYH 9突变引起的，但其病理生理特征仍不清楚。方法：我们研究了一个大的FTNS家族，其中10个组成部分携带错义突变MYH 9决定D1424 H取代。结果如下：所有受影响的受试者均表现为巨血小板减少症和由NMMHC-IIA大聚集体组成的白细胞Dohle样小体，但仅2例受试者出现以蛋白尿和肾衰竭为特征的重大肾脏问题。电子显微镜检查显示足细胞局灶性和节段性消失，足细胞间裂隙隔膜丢失。免疫组化显示NMMHC-IIA在肾小管上皮细胞中的顶端定位和在两名患者中的足细胞染色较少，而在正常上皮细胞中弥漫。3名患者出现稳定的微量血尿，另外5名患者没有肾脏病变，尽管他们携带相同的MYH 9突变。因此，MYH 9突变本身是血小板和白细胞异常的原因，而其他诱发条件和/或环境因素是肾病，白内障和耳聋所必需的。通过观察足细胞成分赋予肾脏选择性渗透特性，我们鉴定了podocin的单体型，并在两名肾病综合征患者中发现了一个特定等位基因的共分离，表明podocin特征与蛋白尿之间存在关系。结论：我们的研究表明，NMMHC-IIA异常的白细胞，血小板和肾功能缺陷的FTNS的发病机制中的主要作用。在所有情况下的基本特征是NMMHC-IIA的聚集和分隔。然而，蛋白尿和足细胞病变是肾功能衰竭患者肾病的标志，podocin可能在这种情况下起一定作用。
Background: Fechtner syndrome (FTNS), also known as Alport-like syndrome, is a rare inherited condition characterized by progressive nephritis, macrothrombocytopenia, Dohle-like leukocyte inclusions, deafness, and cataract. Although it recently was shown that FTNS derives from mutation of MYH9, the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA), its pathophysiological characteristics remain unknown. Methods: We studied a large FTNS family in which 10 components carried a missense mutation of MYH9 determining the D1424H substitution. Results: All affected subjects presented with macrothrombocytopenia and leukocyte Dohle-like bodies consisting of macroaggregates of NMMHC-IIA, but only two subjects had major renal problems characterized by proteinuria and renal failure. Electron microscopy showed focal and segmental effacement of podocytes and loss of the interpodocyte slit diaphragm. Immunohistochemistry showed apical localization of NMMHC-IIA in tubular epithelia and less podocyte staining in the two patients, whereas it was diffuse in normal epithelia. Three patients presented with stable microhematuria, and another five patients had no renal lesions, although they carried the same mutation of MYH9. Therefore, MYH9 mutation per se was responsible for platelet and leukocyte abnormalities, whereas additional predisposing conditions and/or environmental factors are necessary for nephropathy, cataract, and deafness. Looking at podocyte components conferring permselectivity properties to the kidney, we characterized the haplotype of podocin and found cosegregation of one specific allele in the two patients with nephrotic syndrome, suggesting a relationship between podocin features and proteinuria. Conclusion: Our study indicates a major role for the NMMHC-IIA abnormality in the pathogenesis of leukocyte, platelet, and kidney defects in FTNS. The basic feature in all cases is aggregation and compartmentation of NMMHC-IIA. However, proteinuria and podocyte lesions are the hallmark of nephropathy in patients who develop renal failure, and podocin may have some function in this setting.