An atypical Dent's disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes
An atypical Dent's disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes
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DOI：
10.1038/ejhg.2012.225
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发表时间：
2013-06-01
影响因子：
5.2
通讯作者：
Anglani, Franca
中科院分区：
文献类型：
--
作者：
Addis, Maria;Meloni, Cristiana;Anglani, Franca
Dent 病是一种 X 连锁肾小管病，由主要影响 CLCN5 基因的突变引起。 OCRL 基因缺陷（通常在 Lowe 综合征患者中发生突变）已被证明会导致类似 Dent 的表型，称为 Dent 病 2。然而，约 20% 的 Dent 病患者不携带 CLCN5/OCRL 突变。该疾病的遗传异质性伴随着家族间和家族内的表型异质性。我们报告了一例具有非常不寻常表型（畸形特征、眼部异常、生长迟缓、佝偻病、轻度智力低下）的登特氏病病例，其中发现了双基因遗传。检测到两种不同的新型致病突变，均遗传自患者的健康母亲，即 CLCN5 基因 (A249fs*20) 中的截短突变和 OCRL 基因中的供体剪接位点改变 (c. 388+3A>G)。对患者白细胞的 mRNA 分析显示，由于框内外显子 6 跳跃导致 OCRL mRNA 剪接异常，导致蛋白质较短，但中央肌醇 5-磷酸酶结构域和 ASH-RhoGAP 结构域的 C 端侧保持完整。由于完全偏斜的 X 失活，在母亲的白细胞中仅观察到野生型 mRNA。我们的结果首次揭示了上位第二修饰剂对 Dent 病的影响，它可以调节其表达性。我们推测，该患者的严重 Dent 病 2 表型可能是由于两个不同基因突变的成瘾相互作用所致。
Dent's disease is an X-linked renal tubulopathy caused by mutations mainly affecting the CLCN5 gene. Defects in the OCRL gene, which is usually mutated in patients with Lowe syndrome, have been shown to lead to a Dent-like phenotype called Dent disease 2. However, about 20% of patients with Dent's disease carry no CLCN5/OCRL mutations. The disease's genetic heterogeneity is accompanied by interfamilial and intrafamilial phenotypic heterogeneity. We report on a case of Dent's disease with a very unusual phenotype (dysmorphic features, ocular abnormalities, growth delay, rickets, mild mental retardation) in which a digenic inheritance was discovered. Two different, novel disease-causing mutations were detected, both inherited from the patient's healthy mother, that is a truncating mutation in the CLCN5 gene (A249fs*20) and a donor splice-site alteration in the OCRL gene (c. 388+3A>G). The mRNA analysis of the patient's leukocytes revealed an aberrantly spliced OCRL mRNA caused by in-frame exon 6 skipping, leading to a shorter protein, but keeping intact the central inositol 5-phosphatase domain and the C-terminal side of the ASH-RhoGAP domain. Only wild-type mRNA was observed in the mother's leukocytes due to a completely skewed X inactivation. Our results are the first to reveal the effect of an epistatic second modifier in Dent's disease too, which can modulate its expressivity. We surmise that the severe Dent disease 2 phenotype of our patient might be due to an addictive interaction of the mutations at two different genes.