1例OCRL无义突变所致眼脑肾综合征患儿临床及分子遗传学分析

Clinical and genetic analysis of an infant with Lowe syndrome caused by nonsense mutation of OCRL gene

目的探讨1例表现为先天性白内障、先天性青光眼男性患儿的临床表现及遗传学病因。方法收集先证者的临床资料,提取先证者及其双亲外周血基因组DNA,采用全外显子组测序技术(WES)筛选患儿候选可疑致病突变后,通过Sanger DNA测序法进行验证,并利用UCSF chimera软件对候选基因突变所致蛋白功能改变进行生物信息学分析。结果患儿3月龄时临床检测发现有先天性白内障、先天性青光眼;后脑部成像显示双侧侧脑室、第三脑室扩张,脑室旁见片状低密度灶;此外有轻度智力障碍、蛋白尿、隐睾及佝偻病样改变等特征。全外显子组测序结果显示X染色体上OCRL基因(NM_000276)第13外显子存在一个c.1275T>G(p.Y425X)纯合无义突变,导致OCRL基因编码蛋白在第425位酪氨酸(Try)提前终止,破坏了蛋白的完整性。患儿父母表型未见异常,Sanger测序结果也均未发现此突变。蛋白3D结构建模分析发现该p.Y425X终止密码子突变可导致截短蛋白形成,蛋白部分结构丧失,进而影响了蛋白的功能。结论结合临床表现与基因检测结果,患者诊断为眼脑肾综合征(Lowe综合征),OCRL基因c.1275T>G突变是致病基因突变,该突变为首次报道的新生突变,本研究进一步丰富了Lowe综合征的基因突变谱。

Objective To explore the clinical manifestation and genetic pathogeny of an male infant featuring congenital cataract and congenital glaucoma.Methods Clinical data of the case were collected,genomic DNA was extracted from the peripheral blood samples of the case and his parents.Whole exome sequencing was carried out to detect potential variants that can explain proband condition,and suspected variants were validated by Sanger DNA sequencing,and the changes of protein function resulted from the candidate mutations were predicted by UCSF chimera bioinformatic software.Results The phenotypes included congenital cataract and congenital glaucoma when he was 3 mouths.Cranial computer tomography indicated dilatation of bilateral and third ventricles,flaky low-density foci around the ventricles.In addition,mild intellectual impairment,proteinuria,cryptorchidism and rickets were observed.A homozygous nonsense c.1275T>G(p.Y425X)mutation in exon 13 of OCRL gene was detected in the proband,which led to the premature termination of tyrosine(Try)at the position of 425th amino acid of the protein encoded by OCRL gene,thus causing serious function loss of OCRL protein.The phenotype of the parents was normal,and the mutation was not detected in the parents by Sanger sequencing.The protein 3D structural modeling analysis showed that the p.Y425X nonsense mutation could lead to the formation of truncated protein and partial loss of protein structure,which in turn affected the function of the protein.Conclusion Combined clinical manifestations with genetic findings,the patient is diagnosed with Lowe syndrome.OCRL gene c.1275T>G mutation is the pathogenic mutation responsible for the syndrome,which is a de novo mutation previously undescribed.The present study further enriched the gene mutation spectrum of Lowe syndrome.