Heidet Laurence, Bongers Ernie M H F, Sich Mireille, Zhang Shao-Yu, Loirat Chantal, Meyrier Alain, Broyer Michel, Landthaler Gérard, Faller Bernadette, Sado Yoshikazu, Knoers Nine V A M, Gubler Marie-Claire
INSERM U574, Université René Descartes, Hôpital Necker-Enfants Malades, Paris, France.
Am J Pathol. 2003 Jul;163(1):145-55. doi: 10.1016/S0002-9440(10)63638-3.
The nail-patella syndrome (NPS) is characterized by nail and bone abnormalities, associated with glomerular involvement in approximately 40% 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 NPS 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 III collagen antibodies, suggesting a possible regulation of type III collagen expression by LMX1B. The expression of the alpha3 and alpha4 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.
指甲-髌骨综合征（NPS）的特征是指甲和骨骼异常，约40%的患者伴有肾小球受累。典型的肾小球改变包括不规则增厚的肾小球基底膜中有纤维状物质。NPS作为常染色体显性性状遗传，由LIM同源结构域蛋白家族成员LMX1B的杂合功能丧失突变引起。该基因纯合失活的小鼠表现出指甲和骨骼缺陷，与患者中观察到的类似，伴有肾小球异常。在Lmx1b基因敲除小鼠中，已观察到IV型胶原α3和α4链以及足突蛋白和CD2AP（两种对肾小球功能至关重要的足细胞蛋白）在肾小球中的表达大幅降低。这些蛋白质的表达似乎受Lmx1b调控。为了确定足细胞基因表达的这些变化是否参与NPS肾病的发展，我们使用免疫组织学技术分析了7例患有严重肾小球疾病的NPS患者肾脏中的足细胞表型和IV型胶原链的肾脏分布。我们还检查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物质被抗III型胶原抗体特异性标记，提示LMX1B可能对III型胶原表达有调控作用。在这7例患者中，发现IV型胶原α3和α4链以及足突蛋白和CD2AP的表达正常。这些发现表明，LMX1B的杂合突变似乎不会显著影响NPS患者中IV型胶原链、足突蛋白或CD2AP的表达。
