Pathogenicity of a Human Laminin β2 Mutation Revealed in Models of Alport Syndrome
Pathogenicity of a Human Laminin β2 Mutation Revealed in Models of Alport Syndrome
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DOI：
10.1681/asn.2017090997
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发表时间：
2018-03-01
影响因子：
13.6
通讯作者：
Miner, Jeffrey H.
中科院分区：
文献类型：
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作者：
Funk, Steven D.;Bayer, Raymond H.;Miner, Jeffrey H.
皮尔逊综合征是一种先天性肾病综合征，伴有由肾小球基底膜（GBM）的主要成分层粘连蛋白β 2（LAMB 2）突变引起的眼部和神经系统缺陷。人LAMB 2中的致病性错义突变聚集在层粘连蛋白氨基末端（LN）结构域中或附近，层粘连蛋白氨基末端（LN）结构域是层粘连蛋白三聚体和基底膜支架的细胞外聚合所需的结构域。在这里，我们研究了LN结构域错义突变，LAMB 2-S80 R，这是发现在皮尔逊综合征和异常晚发性蛋白尿的患者。生化数据表明，这种突变损害层粘连蛋白聚合，我们假设这是病人的肾病综合征的原因。在基因改变的小鼠中测试这一假设表明，相应的氨基酸变化（LAMB 2-S83 R）本身不是致病性的。然而，LAMB 2-S83 R的表达显著增加了常染色体隐性Alport综合征的Col 4a 3（-/-）小鼠模型中进展为肾衰竭的速率，并且增加了Col 4a 5（+/-）雌性中的蛋白尿，所述雌性表现出由于GBM中胶原蛋白α 3 α 4 α 5（IV）的镶嵌沉积而导致的轻度形式的X连锁Alport综合征。总的来说，这些数据显示了LAMB 2-S80 R的致病性，并提供了通过另一种GBM组分的变异对Alport表型进行遗传修饰的第一个证据。这一发现可以帮助解释在Alport综合征患者中观察到的广泛的Alport综合征发病和严重程度，即使是共享相同COL 4突变的家庭成员。我们的研究结果还显示了使用模式生物来调查怀疑在人类中致病的遗传变异的复杂性。
Pierson syndrome is a congenital nephrotic syndrome with eye and neurologic defects caused by mutations in laminin beta 2 (LAMB2), a major component of the glomerular basement membrane (GBM). Pathogenic missense mutations in human LAMB2 cluster in or near the laminin amino-terminal (LN) domain, a domain required for extracellular polymerization of laminin trimers and basement membrane scaffolding. Here, we investigated an LN domain missense mutation, LAMB2-S80R, which was discovered in a patient with Pierson syndrome and unusually late onset of proteinuria. Biochemical data indicated that this mutation impairs laminin polymerization, which we hypothesized to be the cause of the patient's nephrotic syndrome. Testing this hypothesis in genetically altered mice showed that the corresponding amino acid change (LAMB2-S83R) alone is not pathogenic. However, expression of LAMB2-S83R significantly increased the rate of progression to kidney failure in a Col4a3(-/-) mouse model of autosomal recessive Alport syndrome and increased proteinuria in Col4a5(+/-) females that exhibit a mild form of X-linked Alport syndrome due to mosaic deposition of collagen alpha 3 alpha 4 alpha 5(IV) in the GBM. Collectively, these data show the pathogenicity of LAMB2-S80R and provide the first evidence of genetic modification of Alport phenotypes by variation in another GBM component. This finding could help explain the wide range of Alport syndrome onset and severity observed in patients with Alport syndrome, even for family members who share the same COL4 mutation. Our results also show the complexities of using model organisms to investigate genetic variants suspected of being pathogenic in humans.