Kidney Injury by Variants in the COL4A5 Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis
Kidney Injury by Variants in the COL4A5 Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis
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DOI：
10.3390/ijms20030519
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发表时间：
2019-02-01
影响因子：
5.6
通讯作者：
Gross, Oliver
中科院分区：
文献类型：
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作者：
Frese, Jenny;Kettwig, Matthias;Gross, Oliver
局灶节段性肾小球硬化（FSGS）引起的肾损伤是引起终末期肾脏疾病的最常见的原发性肾小球疾病。肾小球基底膜或狭缝隔膜基因的纯合突变可引起早期肾功能衰竭。杂合子携带者出现肾脏症状较晚，如果有的话。与狭缝横膈膜基因的突变相比，x染色体COL4A5 Alport基因的异型或半合子突变尚未被认为是FSGS肾损伤的主要原因。我们发现了一些意外诊断的FSGS病例：除了x染色体COL4A5型胶原基因突变外，nephrin和podocin多态性加重了肾脏损害，导致幼儿FSGS伴基底膜破裂，杂合子女孩早期肾功能衰竭。我们的病例系列研究结果表明，编码基底膜和狭缝隔膜蛋白的基因在FSGS引起的肾损伤中起协同作用。我们的研究结果表明，肾小球滤过屏障中不同参与者的分子遗传学可用于评估肾损伤的原因。鉴于Alport基因在x染色体上的高频率携带者，分析与足细胞结构、肾小球基底膜和裂隙隔膜组织有关的基因，将进一步提高我们对FSGS发病机制的认识，指导遗传性肾小球肾病的预后和治疗。
Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. In contrast to mutations in slit diaphragm genes, hetero- or hemizygous mutations in the X-chromosomal COL4A5 Alport gene have not yet been recognized as a major cause of kidney injury by FSGS. We identified cases of FSGS that were unexpectedly diagnosed: In addition to mutations in the X-chromosomal COL4A5 type IV collagen gene, nephrin and podocin polymorphisms aggravated kidney damage, leading to FSGS with ruptures of the basement membrane in a toddler and early renal failure in heterozygous girls. The results of our case series study suggest a synergistic role for genes encoding basement membrane and slit diaphragm proteins as a cause of kidney injury due to FSGS. Our results demonstrate that the molecular genetics of different players in the glomerular filtration barrier can be used to evaluate causes of kidney injury. Given the high frequency of X-chromosomal carriers of Alport genes, the analysis of genes involved in the organization of podocyte architecture, the glomerular basement membrane, and the slit diaphragm will further improve our understanding of the pathogenesis of FSGS and guide prognosis of and therapy for hereditary glomerular kidney diseases.