Uncovering Modifier Genes of X-Linked Alport Syndrome Using a Novel Multiparent Mouse Model
Uncovering Modifier Genes of X-Linked Alport Syndrome Using a Novel Multiparent Mouse Model
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DOI：
10.1681/asn.2020060777
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发表时间：
2021-08-01
影响因子：
13.6
通讯作者：
Korstanje, Ron
中科院分区：
文献类型：
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作者：
Takemon, Yuka;Wright, Valerie;Korstanje, Ron
肾脏疾病的严重程度部分由修饰基因决定。这些基因可能是重要的治疗靶点，但在患者群体中难以识别。我们的研究展示了一种新的小鼠遗传方法，使用多样性近交系小鼠来鉴定x连锁阿尔波特综合征的修饰基因。我们确定了几个候选修饰基因，并验证了Fmn1的候选性。我们发现，在Col4a5基因敲除小鼠中，Fmn1表达减少导致蛋白尿减少，肾小球基底膜中足细胞突起减少。我们的方法可以很容易地用于识别其他形式肾脏疾病的修饰基因。80%的x连锁阿尔波特综合征（XLAS）是由COL4A5基因突变引起的。虽然导致AS的基因被很好地描述，但具有相似基因突变的AS患者在肾脏损害的程度和发病年龄方面存在很大差异，这表明修饰基因的活性。方法利用Diversity Outbred mouse资源建立遗传多样性的XLAS雄性和雌性小鼠队列，测量蛋白尿、GFR和基因表达。使用数量性状位点方法，我们绘制了修饰基因，这些修饰基因可以最好地解释在我们不同人群中测量到的潜在表型变异。结果遗传分析发现了几个与蛋白尿和GFR变异相关的位点，包括X染色体上与X失活相关的位点和2号染色体上含有Fmn1的位点。随后对Col4a5基因敲除小鼠Fmn1基因表达减少的分析显示，蛋白尿、足细胞消失和肾小球基底膜足细胞突出减少，这支持了Fmn1作为as修饰基因的候选资格。通过这种新方法，我们通过蛋白尿和GFR测量模拟了人类Alport综合征患者肾脏表型严重程度的变异性。这种方法可以识别肾脏疾病的修饰基因，作为新的治疗靶点。
Significance Statement Kidney disease severity is partly determined by modifier genes. These genes can be important therapeutic targets but are difficult to identify in patient populations. Our study demonstrates a novel mouse genetic approach using Diversity Outbred mice to identify modifier genes for X-linked Alport Syndrome. We identify several candidate modifier genes and validate the candidacy of Fmn1. We show that a decrease in Fmn1 expression in Col4a5 knockout mice leads to a decrease in albuminuria and fewer podocyte protrusions in the glomerular basement membrane. Our approach can be easily adapted to identify modifier genes for other forms of kidney disease.Background Mutations in COL4A5 are responsible for 80% of cases of X-linked Alport Syndrome (XLAS). Although genes that cause AS are well characterized, people with AS who have similar genetic mutations present with a wide variation in the extent of kidney impairment and age of onset, suggesting the activities of modifier genes. Methods We created a cohort of genetically diverse XLAS male and female mice using the Diversity Outbred mouse resource and measured albuminuria, GFR, and gene expression. Using a quantitative trait locus approach, we mapped modifier genes that can best explain the underlying phenotypic variation measured in our diverse population. Results Genetic analysis identified several loci associated with the variation in albuminuria and GFR, including a locus on the X chromosome associated with X inactivation and a locus on chromosome 2 containing Fmn1. Subsequent analysis of genetically reduced Fmn1 expression in Col4a5 knockout mice showed a decrease in albuminuria, podocyte effacement, and podocyte protrusions in the glomerular basement membrane, which support the candidacy of Fmn1 as a modifier gene for AS. Conclusion With this novel approach, we emulated the variability in the severity of kidney phenotypes found in human patients with Alport Syndrome through albuminuria and GFR measurements. This approach can identify modifier genes in kidney disease that can be used as novel therapeutic targets.