Lowe的眼脑肾综合征是一种罕见的X连锁疾病,以先天性白内障为特征,智力迟钝,和近端肾小管病。这种情况是由OCRL基因(位于染色体Xq26.1)的突变引起的,它编码肌醇多磷酸5-磷酸酶。
我们在两个无关的中国男孩中发现了两个新的OCRL突变,每个人都有严重的Lowe综合征表型。一个新的从头缺失(半合子c.659_662delAGGG,患者1中存在p.E220Vfs*29),患者2中存在母系遗传的新剪接突变(半合子c.2257-2A>T)。患者2的肾活检显示轻度系膜增生性肾小球肾炎,轻度局灶性单核细胞浸润,和间质局灶性纤维化。此外,与患有薄基底膜疾病的对照患者相比,患者2的肾脏OCRL-1蛋白表达显著降低.
这项研究报告了两种新的OCRL变异与严重的眼部和神经缺陷相关,尽管只有轻度肾功能不全。根据我们的两名患者和文献综述,OCRL突变与Lowe综合征这种严重表型的基因型-表型相关性提示可能存在错义聚集,删除,中国人群中5-磷酸酶结构域和Rho-GAP结构域的无义突变。
Oculocerebrorenal syndrome of Lowe is a rare X-linked disorder characterized by congenital cataracts, mental retardation, and proximal tubulopathy. This condition is caused by a mutation of OCRL gene (located at chromosome Xq26.1), which encodes an inositol polyphosphate 5-phosphatase.
We identified two novel OCRL mutations in two unrelated Chinese boys, each with a severe phenotype of Lowe syndrome. A novel de novo deletion (hemizygous c.659_662delAGGG, p.E220Vfs*29) was present in patient 1 and a novel splicing mutation (hemizygous c.2257-2A > T) that was maternally inherited was present in patient 2. A renal biopsy in patient 2 indicated mild mesangial proliferative glomerulonephritis, mild focal mononuclear cells infiltration, and interstitial focal fibrosis. Moreover, renal expression of OCRL-1 protein in patient 2 was significantly reduced compared to a control patient with thin basement membrane disease.
This study reports two novel OCRL variants associated with severe ocular and neurologic deficiency, despite only mild renal dysfunction. Based on our two patients and a literature
review, the genotype-phenotype correlation of OCRL mutations with this severe phenotype of Lowe syndrome suggest a possible clustering of missense, deletion, and nonsense mutations in the 5-phosphatase domain and Rho-GAP domain in the Chinese population.