In vivo expression of putative LMX1B targets in nail-patella syndrome kidneys
In vivo expression of putative LMX1B targets in nail-patella syndrome kidneys
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DOI：
10.1016/s0002-9440(10)63638-3
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发表时间：
2003-07-01
影响因子：
6
通讯作者：
Gubler, MC
中科院分区：
文献类型：
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作者：
Heidet, L;Bongers, EMHF;Gubler, MC
指甲-髌骨综合征（NIPs）的特征是指甲和骨骼异常，与肾小球受累有关，约有40%的患者。典型的肾小球改变包括不规则增厚的肾小球基底膜中的纤维状物质。LMX 1B是LIM同源结构域蛋白家族的成员，其功能突变的杂合性缺失导致LMX 1B作为常染色体显性遗传。该基因纯合失活的小鼠表现出与患者相似的指甲和骨骼缺陷，并伴有肾小球异常。在Lmx 1b基因敲除小鼠中观察到IV型胶原的α 3和α 4链以及podocin和CD 2AP（两种对肾小球功能至关重要的足细胞蛋白）的肾小球表达强烈减少。这些蛋白的表达似乎受到Lmx 1b的调控。为了确定足细胞基因表达的这些变化是否参与了肾小球疾病的发展，我们使用免疫组织化学技术，分析了足细胞表型和IV型胶原蛋白链在7例NIPS患者的肾脏中的肾脏分布。我们还检测了肾小球细胞外基质中存在的纤维状物质的性质。肾小球基底膜纤维状材料被特异性标记抗M型胶原抗体，表明LMX 1B可能调节III型胶原表达。IV型胶原的α 3和α 4链以及podocin和CD 2AP的表达在7名患者中被发现是正常的。这些研究结果表明，LMX 1B的杂合突变似乎不会显著影响IV型胶原蛋白链，podocin或CD 2AP的表达。
The nail-patella syndrome (NPS) is characterized by nail and bone abnormalities, associated with glomerular involvement in similar to40% of patients. Typical glomerular changes consist of fibrillar material in the irregularly thickened glomerular basement membrane. NPS is inherited as an autosomal dominant trait and caused by heterozygous loss of function mutations in LMX1B, a member of the LIM homeodomain protein family. Mice with homozygous inactivation of the gene exhibit nail and skeletal defects, similar to those observed in patients, associated with glomerular abnormalities. Strong reduction in the glomerular expression of the alpha3 and alpha4 chains of type IV collagen, and of podocin and CD2AP, two podocyte proteins critical for glomerular function, has been observed in Lmx1b null mice. The expression of these proteins appeared to be regulated by Lmx1b. To determine whether these changes in podocyte gene expression are involved in the development of NPS nephropathy, using immunohistological techniques, we analyzed the podocyte phenotype and the renal distribution of type IV collagen chains in the kidneys of seven NIPS patients with severe glomerular disease. we also examined the nature of the fibrillar material present within the glomerular extracellular matrix. The glomerular basement membrane fibrillar material was specifically labeled with anti-type M collagen antibodies, suggesting a possible regulation of type III collagen expression by LMX1B. The expression of the a3 and a4 chains of type IV collagen, and of podocin and CD2AP, was found to be normal in the seven patients. These findings indicate that heterozygous mutations of LMX1B do not appear to dramatically affect the expression of type IV collagen chains, podocin, or CD2AP in NPS patients.