鳃耳综合征/鳃耳肾综合征的遗传学研究进展

Genetic research progress in branchio-oto syndrome/branchio-oto-renal syndrome

鳃耳综合征(branchio-oto syndrome,BOS)/鳃耳肾综合征(branchio-oto-renal syndrome,BORS)是一种不常见的常染色体显性遗传综合征型疾病,人群发病率约为1/40000,以听力障碍及耳的表现为最主要特征,并伴有肾脏畸形及鳃裂囊肿或瘘管等症状。耳畸形是BOS/BORS最明显的临床表现之一,包括外耳、中耳、内耳畸形和听力障碍。听力障碍又分为传导性、感音神经性或混合性,程度可轻可重。颞骨影像学可以帮助临床医生诊断中耳和内耳畸形。直接测序结合二代测序(next generation sequencing,NGS)、多重连接扩增(multiplex ligation-dependent probe amplification,MLPA)和比较基因组杂交(array-based comparative genomic hybridization,aCGH)等技术可有效筛选及鉴定BOS/BORS致病基因及突变类型。EYA1基因突变是引起BOS/BORS最主要的遗传学病因,约40%的患者携带此基因突变,目前已在不同人群中报道了240种EYA1基因致病突变,包括移码、无义、错义、异常剪接、缺失和复杂重排。人类内源性反转录病毒序列(human endogenous retroviral sequences,HERV)可能在介导非等位同源重组引起的EYA1染色体片段缺失突变中发挥重要作用。EYA1编码一种与SIX1转录因子协同作用的磷酸酶反式激活因子,参与颅感觉神经的发生和鳃弓衍生器官的发育,调节外耳、中耳和内耳形态和功能的正常分化。此外,SIX1和SIX5基因的致病突变也会导致BOS/BORS,以上3种基因的突变可能通过破坏SIX1-EYA1、SIX5-EYA1蛋白质结合或SIX1-DNA的结合而致病,但SIX5基因在BORS致病中的作用仍需进一步验证。

Branchio-oto syndrome(BOS)/branchio-oto-renal syndrome(BORS)is a kind of autosomal dominant heterogeneous disorder.These diseases are mainly characterized by hearing impairment and abnormal phenotype of ears,accompanied by renal malformation and branchial cleft anomalies including cyst or fistula,with an incidence of 1/40000 in human population.Otic anormalies are one of the most obvious clinical manifestations of BOS/BORS,including deformities of external,middle,inner ears and hearing loss with conductive,sensorineural or mix,ranging from mild to profound loss.Temporal bone imaging could assist in the diagnosis of middle ear and inner ear malformations for clinicians.Multiple methods including direct sequencing combined with next generation sequencing(NGS),multiplex ligation-dependent probe amplification(MLPA),or arraybased comparative genomic hybridization(a CGH)can effectively screen and identify pathogenic genes and/or variation types of BOS/BORS.About 40%of patients with BOS/BORS carry aberrations of EYA1 gene which is the most important cause of BOS/BORS.A total of 240 kinds of pathogenic variations of EYA1 have been reported in different populations so far,including frameshift,nonsense,missense,aberrant splicing,deletion and complex rearrangements.Human Endogenous Retroviral sequences(HERVs)may play an important role in mediating EYA1 chromosomal fragment deletion mutations caused by nonallelic homologous recombination.EYA1 encodes a phosphatase-transactivator cooperated with transcription factors of SIX1,participates in cranial sensory neurogenesis and development of branchial arch-derived organs,then regulates the morphological and functional differentiation of the outer ear,middle ear and inner ear toward normal tissues.In addition,pathogenic mutations of SIX1 and SIX5 genes can also cause BOS/BORS.Variations of these genes mentioned above may cause disease by destroying the bindings between SIX1-EYA1,SIX5-EYA1 or SIX1-DNA.However,the role of SIX5 gene in the pathogenesis of BORS needs further verification.