Incomplete cryptic splicing by an intronic mutation of OCRL in patients with partial phenotypes of Lowe syndrome
Incomplete cryptic splicing by an intronic mutation of OCRL in patients with partial phenotypes of Lowe syndrome
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DOI：
10.1038/s10038-020-0773-3
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发表时间：
2020-05-19
影响因子：
3.5
通讯作者：
Harita, Yutaka
中科院分区：
文献类型：
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作者：
Nakano, Eiji;Yoshida, Amine;Harita, Yutaka
OCRL基因突变导致Lowe综合征，其特征是先天性白内障、婴儿低眼压伴智力低下、肾小管功能障碍和只影响肾脏的Dent-2疾病。虽然很少有介于这些疾病之间的中间表型的患者被报道，但表型变异的潜在机制尚不清楚。我们在OCRL基因第20内含子中发现了一个内含子突变c.2257-5G>；A，该突变发生在一位患有非典型Lowe综合征的哥哥和一位仅有肾脏表型的弟弟身上。这种突变产生了一个剪接受体基序，在第20和21外显子的交界处伴随着一个神秘的提前终止密码子。突变导致了不完全的选择性剪接，这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选择性剪接转录本。在患者的细胞中，交替剪接的转录本被无义介导的衰退降解，野生型转录本显著减少，但并未完全耗尽。这些发现表明，内含子突变产生的不完全选择性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。
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.