Onset mechanism of a female patient with Dent disease 2
Onset mechanism of a female patient with Dent disease 2
复制标题
女性Dent病患者发病机制2
DOI：
10.1007/s10157-020-01926-4
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发表时间：
2020
影响因子：
2.3
通讯作者：
Manabe Atsushi
中科院分区：
文献类型：
--
作者：
Okamoto Takayuki;Sakakibara Nana;Nozu Kandai;Takahashi Toshiyuki;Hayashi Asako;Sato Yasuyuki;Nagano China;Matsuo Masafumi;Iijima Kazumoto;Manabe Atsushi
大约15%的Dent病患者在Xq 25 -26的OCRL基因中存在致病性变异，这种情况被称为Dent病2（Dent-2）。Dent-2患者有时表现出轻度的Lowe综合征肾外特征，如轻度智力迟钝，表明Dent-2代表了Lowe综合征的一种轻度形式。到目前为止，8名女性患者与Lowe综合征已被报道，但没有女性Dent-2 patients have been reported.MethodsIn this study，我们进行了基因检测的第一位女性Dent-2患者，以检测存在的OCRL变异。通过体内、体外和计算机模拟试验证明了异常剪接，通过HUMARA分析，使用基因组DNA和RNA表达分析，评估了我们的患者和三名Lowe患者的无症状母亲的OCRL变异和偏斜X染色体失活（XCI）。bp插入，在外显子16中产生截短突变r.1602_1603ins（169）（p.Val535Glyfs*6）。从该患者中获得的白细胞的HUMARA测定显示不完全偏斜的XCI（非极度偏斜）。另一方面，3名Lowe患者的无症状母亲表现出随机XCI。这些结果可能导致我们的病人的Dent-2 phenotype.ConclusionsThis是第一次报告的女性患者临床和遗传诊断与Dent-2引起的OCRL杂合剪接位点变异和歪斜XCI。偏斜XCI可能是与Lowe综合征和Dent-2女性患者表型多样性相关的因素之一。
BackgroundApproximately 15% of patients with Dent disease have pathogenic variants in theOCRLgene on Xq25-26, a condition that is referred to as Dent disease 2 (Dent-2). Dent-2 patients sometimes show mild extrarenal features of Lowe syndrome, such as mild mental retardation, suggesting that Dent-2 represents a mild form of Lowe syndrome. To date, eight female patients with Lowe syndrome have been reported, but no female Dent-2 patients have been reported.MethodsIn this study, we performed genetic testing of the first female Dent-2 patient to detect the presence of anOCRLvariant. Aberrant splicing was demonstrated by in vivo, in vitro, and in silico assays, and skewed X-chromosome inactivation (XCI) in our patient and asymptomatic mothers of three Lowe patients with the heterozygousOCRLvariant was evaluated by HUMARA assays using genomic DNA and RNA expression analysis.ResultsOur patient had anOCRLheterozygous intronic variant of c.1603-3G > C in intron 15 that led to a 169-bp insertion in exon 16, yielding the truncating mutation r.1602_1603ins (169) (p.Val535Glyfs*6) in exon 16. HUMARA assays of leukocytes obtained from this patient demonstrated incompletely skewed XCI (not extremely skewed). On the other hand, the asymptomatic mothers of 3 Lowe patients demonstrated random XCI. These results may lead to our patient’s Dent-2 phenotype.ConclusionsThis is the first report of a female patient clinically and genetically diagnosed with Dent-2 caused by anOCRLheterozygous splicing site variant and skewed XCI. Skewed XCI may be one of the factors associated with phenotypic diversity in female patients with Lowe syndrome and Dent-2.