Nakanishi K, Iijima K, Kuroda N, Inoue Y, Sado Y, Nakamura H, Yoshikawa N
Department of Pediatrics, Kobe University School of Medicine, Japan.
J Am Soc Nephrol. 1998 Aug;9(8):1433-40. doi: 10.1681/ASN.V981433.
X-Linked Alport syndrome is caused by mutations in the type IV collagen alpha5 chain gene. Male patients usually develop end-stage renal disease, whereas female patients have more variable phenotypes from asymptomatic hematuria to end-stage renal disease. The variable phenotypes in female patients may be attributable to different X-chromosome inactivation patterns. Therefore, the correlation between disease severity and the degree of alpha5 chain expression in the epidermal basement membrane of female patients with X-linked Alport syndrome was examined. To estimate the disease severity in X-linked Alport syndrome, the ratios of protein to creatinine in single voided urine samples were used. Expression of the alpha5 chain in the epidermal basement membrane was examined by an indirect immunofluorescence method using an anti-alpha5 chain monoclonal antibody. A total of 25 female patients with X-linked Alport syndrome from 17 families was examined. Multiple regression analysis using disease severity as the response variable, and age, family history of nephritis, female and male family history of end-stage renal disease, serum creatinine concentration, and alpha5(IV) expression ratio in the epidermal basement membrane as explanatory variables showed that only alpha5(IV) expression ratio was a significant factor, and that it showed a highly significant negative association with disease severity (adjusted r2=0.71, P=0.0001). These findings suggest that variable alpha5 chain expression, possibly caused by different X-inactivation patterns, is responsible for the variable disease severity in female patients with X-linked Alport syndrome, and that immunohistochemical examination of alpha5 chain expression in the epidermal basement membrane may be a simple and useful method for predicting patient outcome.
X连锁遗传性Alport综合征由IV型胶原α5链基因突变引起。男性患者通常会发展为终末期肾病，而女性患者的表型则更为多样，从无症状血尿到终末期肾病都有。女性患者表型的多样性可能归因于不同的X染色体失活模式。因此，研究了X连锁遗传性Alport综合征女性患者疾病严重程度与表皮基底膜中α5链表达程度之间的相关性。为了评估X连锁遗传性Alport综合征的疾病严重程度，使用单次晨尿样本中蛋白质与肌酐的比值。通过使用抗α5链单克隆抗体的间接免疫荧光法检测表皮基底膜中α5链的表达。共检测了来自17个家庭的25名X连锁遗传性Alport综合征女性患者。以疾病严重程度作为应变量，年龄、肾炎家族史、女性和男性终末期肾病家族史、血清肌酐浓度以及表皮基底膜中α5(IV)表达比值作为解释变量进行多元回归分析，结果显示只有α5(IV)表达比值是一个显著因素，并与疾病严重程度呈高度显著的负相关（调整后的r2=0.71，P=0.0001）。这些发现表明，可能由不同的X失活模式导致的α5链表达差异，是X连锁遗传性Alport综合征女性患者疾病严重程度不同的原因，并且对表皮基底膜中α5链表达进行免疫组化检测可能是预测患者预后的一种简单而有用的方法。
