A Splicing Variant in OCRL Gene Might Explain the Second Case of Lowe Syndrome in Iran

M. Houshmand, G. Babamohammadi, H. Moazzeni, Ahmad Reza Salehi Chaleshtori, M. Akbari
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Abstract

: Lowe syndrome is a condition that primarily affects eyes, brain, and kidneys. This disorder follows X-linked recessive mode of inheritance and it occurs in males mainly. Mutations in OCRL (located at Xq25) gene can cause accumulation of phosphatidylinositol bisphosphate and disturbed actin cytoskeleton remodeling. There are 268 mutations in OCRL gene causing Lowe syndrome or Dent disease 2 in HGMD database, however 10 - 20% of Lowe syndrome suspects remain undiagnosed at molecular level. Here we present a male case of Lowe syndrome with characteristic features. Comprehensive clinical examination and genetic counseling were performed. Sanger sequencing was employed to investigate the possible OCRL mutations and we identified a donor splice site variant (NM-000276: c.2469 + 1G > A) in hemizygous state. This is a pathogenic variant according to the ACMG standards and guidelines and might explain the clinical features of the patient. This result is in accordance with the clinical diagnosis of Lowe syndrome and it is absent from ExAC, 1000 G, Iranome, GME, gnomAD Genome databases of healthy controls. In-silico analysis of this splicing variant revealed that the position is highly conserved between species. Splicing prediction tools predicted some changes in splicing pattern of the OCRL transcript, elimination of some protein features, and malfunctioning the OCRL protein as a consequence of this variant. Accordingly, we proposed the c.2469 + 1G > A variant might explain the clinical features in studied patient and be employed for prenatal diagnosis of Lowe syndrome in the family.
ocl基因剪接变异可能解释伊朗第二例洛氏综合征
罗氏综合症是一种主要影响眼睛、大脑和肾脏的疾病。该病为x连锁隐性遗传,多见于男性。ocl(位于Xq25)基因突变可引起磷脂酰肌醇二磷酸积累和肌动蛋白细胞骨架重塑紊乱。HGMD数据库中有268个ocl基因突变导致Lowe综合征或Dent病2,但10 - 20%的Lowe综合征疑似患者仍未在分子水平上得到诊断。在这里我们提出一个男性的洛氏综合症的特点。进行全面的临床检查和遗传咨询。采用Sanger测序方法对可能的ocl突变进行了研究,并鉴定出一个半合子状态的供体剪接位点变异(NM-000276: c.2469 + 1G > a)。根据ACMG标准和指南,这是一种致病变异,可能解释了患者的临床特征。该结果符合Lowe综合征的临床诊断,且在健康对照的ExAC、1000g、Iranome、GME、gnomAD基因组数据库中均不存在。对该剪接变异的硅分析表明,该位置在物种之间高度保守。剪接预测工具预测了ocl转录物剪接模式的一些变化,一些蛋白质特征的消除,以及由于这种变异而导致的ocl蛋白功能失调。因此,我们认为c.2469 + 1G > A变异可能解释了所研究患者的临床特征,并可用于家庭中Lowe综合征的产前诊断。
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