Mouse Model for Lowe Syndrome/Dent Disease 2 Renal Tubulopathy
Mouse Model for Lowe Syndrome/Dent Disease 2 Renal Tubulopathy
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DOI：
10.1681/asn.2010050565
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发表时间：
2011-03-01
影响因子：
13.6
通讯作者：
Nussbaum, Robert L.
中科院分区：
文献类型：
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作者：
Bothwell, Susan P.;Chan, Emily;Nussbaum, Robert L.
罗氏眼脑肾综合征是一种以先天性白内障、认知障碍和近端肾小管功能障碍为特征的x连锁疾病。这种综合征和Dent病2都是由编码II型磷脂酰肌醇二磷酸5-磷酸酶的OCRL基因的功能丧失突变引起的。然而，缺乏ocl的小鼠不受影响，我们认为这反映了人类和小鼠在应对酶缺乏方面的差异。Inpp5b和Inpp5b是在小鼠和人类中分别编码另一种II型磷酸肌肽5-磷酸酶的常染色体旁系基因，它们可能解释了这两个物种的不同表型，因为它们在各自的基因组中与ocl和ocl最接近，但在表达和剪接方面在两个物种之间存在差异。在这里，我们产生了表达INPP5B而不表达INPP5B的ocl（-/-）小鼠。与人类综合征相似，所有患者均表现出出生后生长减慢、低分子量蛋白尿和氨基酸尿。因此，我们通过在已经携带突变疾病基因的小鼠中人源化修饰物平行物，创建了ocl和Dent病2小管病变的动物模型
The Lowe oculocerebrorenal syndrome is an X-linked disorder characterized by congenital cataracts, cognitive disability, and proximal tubular dysfunction. Both this syndrome and Dent Disease 2 result from loss-of-function mutations in the OCRL gene, which encodes a type II phosphatidylinositol bisphosphate 5-phosphatase. Ocrl-deficient mice are unaffected, however, which we believe reflects a difference in how humans and mice cope with the enzyme deficiency. Inpp5b and INPP5B, paralogous autosomal genes that encode another type II phosphoinositide 5-phosphatase in mice and humans, respectively, might explain the distinct phenotype in the two species because they are the closest paralogs to Ocrl and OCRL in their respective genomes yet differ between the two species with regard to expression and splicing. Here, we generated Ocrl(-/-) mice that express INPP5B but not Inpp5b. Similar to the human syndromes, all showed reduced postnatal growth, low molecular weight proteinuria, and aminoaciduria. Thus, we created an animal model for OCRL and Dent Disease 2 tubulopathy by humanizing a modifier paralog in mice already carrying the mutant disease gene