Department of Biomedical and Biotechnological Sciences, University of Cagliari, Cagliari, Italy.
Eur J Hum Genet. 2013 Jun;21(6):687-90. doi: 10.1038/ejhg.2012.225. Epub 2012 Oct 10.
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.
Dent 病是一种 X 连锁的肾小管病，主要由影响 CLCN5 基因的突变引起。OCRL 基因的缺陷，通常在 Lowe 综合征患者中发生突变，已被证明会导致类似于 Dent 的表型，称为 Dent 病 2。然而，大约 20%的 Dent 病患者没有 CLCN5/OCRL 突变。该疾病的遗传异质性伴随着家族内和家族间的表型异质性。我们报告了一例 Dent 病的非常不寻常的表型（畸形特征、眼部异常、生长迟缓、佝偻病、轻度智力障碍），发现存在双基因遗传。检测到两种不同的新的致病突变，均从患者健康的母亲遗传而来，即 CLCN5 基因中的截断突变（A249fs*20）和 OCRL 基因中的供体位点剪接改变（c.388+3A>G）。患者白细胞的 mRNA 分析显示，由于内含子 6 跳跃导致异常剪接的 OCRL mRNA，导致较短的蛋白质，但保持完整的肌醇 5-磷酸酶结构域和 ASH-RhoGAP 结构域的 C 末端。由于完全偏性 X 失活，仅在母亲的白细胞中观察到野生型 mRNA。我们的结果是首次揭示 Dent 病中第二个修饰基因的上位效应，也可以调节其表型。我们推测，我们患者严重的 Dent 病 2 表型可能是由于两个不同基因的突变的累加相互作用所致。
