Mutations of OCRL cause Lowe syndrome, which is characterised by congenital cataracts, infantile hypotonia with mental retardation, and renal tubular dysfunction and Dent-2 disease, which only affects the kidney. While few patients with an intermediate phenotype between these diseases have been reported, the mechanism underlying variability in the phenotype is unclear. We identified an intronic mutation, c.2257-5G>A, in intron 20 of OCRL in an older brother with atypical Lowe syndrome without eye involvement and a younger brother with renal phenotype alone. This mutation created a splice acceptor motif that was accompanied by a cryptic premature termination codon at the junction of exons 20 and 21. The mutation caused incomplete alternative splicing, which created a small amount of wild-type transcript and a relatively large amount of alternatively spliced transcript with a premature termination codon. In the patients' cells, the alternatively spliced transcript was degraded by nonsense-mediated decay and the wild-type transcript was significantly decreased, but not completely depleted. These findings imply that an intronic mutation creating an incomplete alternative splicing acceptor site results in a relatively low level of wild-type OCRL mRNA expression, leading to partial phenotypes of Lowe syndrome.

中文翻译：

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具有部分Lowe综合征表型的患者中OCRL内含子突变导致的不完全隐秘剪接。

OCRL突变会导致Lowe综合征，其特征是先天性白内障，伴有智力低下的婴儿肌张力低下，肾小管功能障碍和Dent-2疾病，仅影响肾脏。虽然很少有患者在这些疾病之间出现中间表型的报道，但表型变异的潜在机制尚不清楚。我们在一个没有眼睛受累的非典型Lowe综合征的哥哥和一个单独有肾脏表型的哥哥中鉴定了OCRL内含子20的内含子突变，c.2257-5G> A。此突变产生了一个剪接受体基序，并在外显子20和21的交界处伴有一个秘密的过早终止密码子。该突变导致不完整的选择性剪接，产生了少量的野生型转录本和相对大量的带有提前终止密码子的剪接转录本。在患者细胞中，选择性剪接的转录本由于无意义介导的衰变而降解，野生型转录本显着降低，但并未完全耗尽。这些发现暗示内含子突变产生不完整的替代剪接受体位点导致野生型OCRL mRNA表达水平相对较低，从而导致Lowe综合征的部分表型。