BACKGROUND Lowe syndrome and Dent-2 disease are caused by mutations in the OCRL gene, which encodes for an inositol 5-phosphatase. The renal phenotype associated with OCRL mutations typically comprises a selective proximal tubulopathy, which can manifest as Fanconi syndrome in the most extreme cases. METHODS Here, we report a 12-year-old male with nephrotic-range proteinuria and focal segmental glomerulosclerosis on renal biopsy. As a glomerular pathology was suspected, extensive investigation of tubular function was not performed. RESULTS Surprisingly, whole exome sequencing identified a genetic variant in OCRL (c1467-2A>G) that introduced a novel splice mutation leading to skipping of exon 15. In situ hybridisation of adult human kidney tissue and zebrafish larvae showed OCRL expression in the glomerulus, supporting a role for OCRL in glomerular function. In cultured podocytes, we found that OCRL associated with the linker protein IPIP27A and CD2AP, a protein that is important for maintenance of the podocyte slit diaphragm. CONCLUSION Taken together, this work suggests a previously under-appreciated role for OCRL in glomerular function and highlights the importance of investigating tubular function in patients with persistent proteinuria.

中文翻译：

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OCRL在肾小球功能和疾病中的作用。

背景Lowe综合征和Dent-2病是由编码肌醇5-磷酸酶的OCRL基因突变引起的。与OCRL突变相关的肾脏表型通常包括选择性近端肾小管病变，在最极端的情况下可表现为Fanconi综合征。方法在这里，我们报道了一名12岁的男性，在肾脏活检中患有肾病范围蛋白尿和局灶性节段性肾小球硬化。由于怀疑是肾小球病理，因此未进行肾小管功能的广泛研究。结果令人惊讶的是，整个外显子组测序鉴定出OCRL中的遗传变异（c1467-2A> G），该变异引入了导致剪接外显子15的新剪接突变。成年人类肾脏组织和斑马鱼幼虫的原位杂交显示肾小球中OCRL表达，支持OCRL在肾小球功能中的作用。在培养的足细胞中，我们发现OCRL与连接蛋白IPIP27A和CD2AP相关，该蛋白对于维持足细胞裂隙隔膜很重要。结论综上所述，这项工作表明OCRL在肾小球功能中的作用先前未被重视，并强调了研究持续性蛋白尿患者肾小管功能的重要性。