Different Phenotypes of the Two Chinese Probands with the Same c.889G>A (p.C162Y) Mutation in COCH Gene Verify Different Mechanisms Underlying Autosomal Dominant Nonsyndromic Deafness 9.
Different Phenotypes of the Two Chinese Probands with the Same c.889G>A (p.C162Y) Mutation in COCH Gene Verify Different Mechanisms Underlying Autosomal Dominant Nonsyndromic Deafness 9.
复制标题
COCH 基因中具有相同 c.889G>A (p.C162Y) 突变的两个中国先证者的不同表型验证了常染色体显性非综合征性耳聋的不同机制 9.
DOI：
10.1371/journal.pone.0170011
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Wang Q;Fei P;Gu H;Zhang Y;Ke X;Liu Y
通过对两个中国DFNA 9家系的表型分析和功能检测，探讨了LCCL和vWFA结构域突变的不同发病机制。使用针对生育相关基因的下一代靶向测序来鉴定家族#208中先证者的突变。对具有相同p.C162Y突变的家系#208和家系#32的先证者随访3年以上，使用纯音测听、热量测试、耳蜗电图、前庭诱发肌源性电位和视频头脉冲测试评估听力损失和前庭功能障碍的进展。通过体外细胞实验测试了正常切割的破坏以产生分泌的LCCL结构域片段和形成突变体蜗蛋白聚集体的倾向。两个家族表现出不同的临床症状。家族#32被鉴定为具有早发性、进行性感音神经性听力损失，类似于在vWFA结构域中具有cochlin突变的DFNA 9患者的症状。家族#208的先证者患有迟发性复发性阵发性眩晕发作和进行性听力恶化，与LCCL结构域中cochlin突变的患者症状相似。因此，我们认为LCCL结构域片段的断裂可能导致前庭功能障碍，vWFA结构域突变引起的突变cochlin的聚集是早发性听力损失的原因。p.C162Y突变导致LCCL结构域片段切割的破坏或突变cochlin的聚集，导致两个家族中不同的表型。这项研究表明，具有相同基因型的DFNA9家族可能具有显著不同的表型。cochlin的突变位点与不同表型的病理机制有关。
By analyzing the different phenotypes of two Chinese DFNA9 families with the same mutation located in the intervening region between the LCCL and vWFA domains of cochlin and testing the functional changes in the mutant cochlin, we investigated the different pathogeneses for mutations in LCCL and vWFA domains. Targeted next-generation sequencing for deafness-related genes was used to identify the mutation in the proband in family #208. The probands of family #208 and family #32 with the same p.C162Y mutation were followed for more than 3 years to evaluate the progression of hearing loss and vestibular dysfunction using pure-tone audiometry, caloric testing, electrocochleogram, vestibular-evoked myogenic potential, and video head-impulse test. The disruption of normal cleavage to produce secreted LCCL domain fragments and the tendency to form aggregations of mutant cochlins were tested by in vitro cell experiments. The two families showed different clinical symptoms. Family #32 was identified as having early-onset, progressive sensorineural hearing loss, similar to the symptoms in DFNA9 patients with cochlin mutations in the vWFA domain. The proband of family #208 endured late-onset recurrent paroxysmal vertigo attacks and progressively deteriorating hearing, similar to symptoms in those with cochlin mutations in the LCCL domain. We therefore suggest that the disrupted cleavage of the LCCL domain fragment is likely to cause vestibular dysfunction, and aggregation of mutant cochlin caused by mutations in the vWFA domain is responsible for early-onset hearing loss. The p.C162Y mutation causes either disruption of LCCL domain fragment cleavage or aggregation of mutant cochlin, resulting in the different phenotypes in the two families. This study demonstrates that DFNA9 families with the same genotype may have significantly different phenotypes. The mutation site in cochlin is related to the pathological mechanism underlying the different phenotypes.