Human laminin β2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities
Human laminin β2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities
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人类层粘连蛋白β2缺乏症会导致伴有间质硬化的先天性肾病和明显的眼部畸形
DOI：
10.1093/hmg/ddh284
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发表时间：
2004-11-01
影响因子：
3.5
通讯作者：
Reis, A
中科院分区：
文献类型：
--
作者：
Zenker, M;Aigner, T;Reis, A
先天性肾病综合征（CNS）具有临床和遗传异质性，WT1、NPHS1和NPHS2突变占部分病例。我们最近描述了一种新的常染色体隐性实体，包括中枢神经系统弥漫性系膜硬化和明显的眼部异常，以小眼珠为主要临床特征（Pierson综合征）。基于对染色体3p14-p22标记的纯合定位，我们在5个无亲缘关系的家族患者中发现了LAMB2的纯合或复合杂合突变。大多数疾病相关等位基因是截断突变。通过免疫组织化学和western blotting，我们可以证明各自的LAMB2突变导致肾和其他组织中层粘连蛋白β 2表达的丧失。已知层粘连蛋白β 2在肾小球基底膜（GBM）中大量表达，它被认为在足细胞足突的锚定和分化中起关键作用。据报道，Lamb2基因敲除小鼠表现出先天性肾病，并伴有视网膜和神经肌肉连接的异常。通过研究未受影响的对照组眼层粘连蛋白β 2的表达，我们发现眼内肌中最强的表达与患者观察到的睫状肌和瞳孔肌的特征性发育不全相对应。此外，我们提出了LAMB2缺陷导致视力和神经发育严重损害的第一个临床证据。我们目前的数据表明，人类层粘连蛋白β 2缺乏与这种特殊的眼肾综合征一致且特异性相关。此外，GBM和足细胞足突之间的分子界面成分成为孤立性和综合征性中枢神经系统的潜在候选者。
Congenital nephrotic syndrome (CNS) is clinically and genetically heterogeneous, with mutations in WT1, NPHS1 and NPHS2 accounting for part of cases. We recently delineated a new autosomal recessive entity comprising CNS with diffuse mesangial sclerosis and distinct ocular anomalies with microcoria as the leading clinical feature (Pierson syndrome). On the basis of homozygosity mapping to markers on chromosome 3p14-p22, we identified homozygous or compound heterozygous mutations of LAMB2 in patients from five unrelated families. Most disease-associated alleles were truncating mutations. Using immunohistochemistry and western blotting we could demonstrate that the respective LAMB2 mutations lead to loss of laminin beta2 expression in kidney and other tissues studied. Laminin beta2 is known to be abundantly expressed in the glomerular basement membrane (GBM) where it is thought to play a key role in anchoring as well as differentiation of podocyte foot processes. Lamb2 knockout mice were reported to exhibit congenital nephrosis in association with anomalies of retina and neuromuscular junctions. By studying ocular laminin beta2 expression in unaffected controls, we detected the strongest expression in the intraocular muscles corresponding well to the characteristic hypoplasia of ciliary and pupillary muscles observed in patients. Moreover, we present first clinical evidence of severe impairment of vision and neurodevelopment due to LAMB2 defects. Our current data suggest that human laminin beta2 deficiency is consistently and specifically associated with this particular oculorenal syndrome. In addition, components of the molecular interface between GBM and podocyte foot processes come in the focus as potential candidates for isolated and syndromic CNS.