Congenital hearing impairment associated with peripheral cochlear nerve dysmyelination in glycosylation-deficient muscular dystrophy
Congenital hearing impairment associated with peripheral cochlear nerve dysmyelination in glycosylation-deficient muscular dystrophy
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DOI：
10.1371/journal.pgen.1008826
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发表时间：
2020-05-01
期刊：
影响因子：
4.5
通讯作者：
Ueyama, Takehiko
中科院分区：
文献类型：
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作者：
Morioka, Shigefumi;Sakaguchi, Hirofumi;Ueyama, Takehiko
作者摘要听力损失（HL）是人类最常见的感觉障碍和异质性疾病之一。高达60%的HL病例是由遗传因素引起的，大约30%的遗传性HL病例是综合征性的。尽管 400-700 种遗传综合征与感音神经性 HL (SNHL) 相关（由于从耳蜗到大脑的神经通路出现问题而引起），但已知只有约 45 个基因与综合征性 HL 相关。肌营养不良症 (MD) 是一种神经肌肉疾病，其特征是骨骼肌进行性退化并伴有非肌肉症状。 MD-肌营养不良症 (MD-DG) 是由 α-肌营养不良聚糖异常糖基化引起的 MD 亚型，具有广泛的非肌肉症状。尽管 MD-DG 亚型数量不断增加（至少 18 种），但尚无全面的研究调查 MD-DG 中的 SNHL。在这里，我们发现，在两种 MD-DG 小鼠模型（3 型和 6 型）和 MD-DG 患者（4 型）中，听力障碍与由肌营养不良蛋白-肌营养不良聚糖复合物受损引起的耳蜗神经周围段髓鞘形成异常相关。这是第一个调查 MD-DG 中 SNHL 的综合研究。我们的研究结果可能为理解遗传性综合征性听力障碍的致病特征和机制提供新的见解。听力损失（HL）是人类最常见的感觉障碍和病因学和遗传异质性疾病之一。肌营养不良症 (MD) 是一种神经肌肉疾病，其特征是骨骼肌进行性退化并伴有非肌肉症状。 α-肌营养不良聚糖的异常糖基化会导致至少 18 种 MD 亚型，目前被归类为 MD-肌营养不良聚糖病 (MD-DG)，具有广泛的非肌肉症状。尽管 MD-DG 亚型的数量不断增加，并且有关其分子发病机制的证据也越来越多，但尚未有全面的研究调查 MD-DG 中的感音神经性 HL (SNHL)。在这里，我们发现两种 MD-DG 小鼠模型，即 Large(myd/myd) 和 POMGnT1-KO 小鼠，在听性脑干反应 (ABR) 中表现出先天性、非进行性和轻至中度 SNHL，并伴有 I 波潜伏期延长。在耳蜗神经的外周部分发现了严重异常的髓鞘形成，该部分富含糖基化 α-肌营养不良聚糖-层粘连蛋白复合物和由“神经胶质穹顶”划分。此外，福山先天性MD（一种MD-DG）患者也有潜在的SNHL，ABR中I波潜伏期延长。总的来说，这些发现表明，与耳蜗神经周围段雪旺细胞介导的髓鞘形成受损相关的听力障碍是 MD-DG 的一个显着症状。
Author summaryHearing loss (HL) is one of the most common sensory impairments and heterogeneous disorders in humans. Up to 60% of HL cases are caused by genetic factors, and approximately 30% of genetic HL cases are syndromic. Although 400-700 genetic syndromes are associated with sensorineural HL (SNHL), caused due to problems in the nerve pathways from the cochlea to the brain, only about 45 genes are known to be associated with syndromic HL. Muscular dystrophies (MDs) are neuromuscular disorders characterized by progressive degeneration of skeletal muscle accompanied by non-muscular symptoms. MD-dystroglycanopathy (MD-DG), caused by aberrant glycosylation of alpha-dystroglycan, is an MD subtype with a wide spectrum of non-muscular symptoms. Despite a growing number of MD-DG subtypes (at least 18), no comprehensive study has investigated SNHL in MD-DG. Here, we found that hearing impairment was associated with abnormal myelination of the peripheral segment of the cochlear nerve caused by impaired dystrophin-dystroglycan complex in two mouse models (type 3 and 6) of MD-DG and in patients (type 4) with MD-DG. This is the first comprehensive study investigating SNHL in MD-DG. Our findings may provide new insights into understanding the pathogenic characteristics and mechanisms underlying inherited syndromic hearing impairment.Hearing loss (HL) is one of the most common sensory impairments and etiologically and genetically heterogeneous disorders in humans. Muscular dystrophies (MDs) are neuromuscular disorders characterized by progressive degeneration of skeletal muscle accompanied by non-muscular symptoms. Aberrant glycosylation of alpha-dystroglycan causes at least eighteen subtypes of MD, now categorized as MD-dystroglycanopathy (MD-DG), with a wide spectrum of non-muscular symptoms. Despite a growing number of MD-DG subtypes and increasing evidence regarding their molecular pathogeneses, no comprehensive study has investigated sensorineural HL (SNHL) in MD-DG. Here, we found that two mouse models of MD-DG, Large(myd/myd) and POMGnT1-KO mice, exhibited congenital, non-progressive, and mild-to-moderate SNHL in auditory brainstem response (ABR) accompanied by extended latency of wave I. Profoundly abnormal myelination was found at the peripheral segment of the cochlear nerve, which is rich in the glycosylated alpha-dystroglycan-laminin complex and demarcated by "the glial dome." In addition, patients with Fukuyama congenital MD, a type of MD-DG, also had latent SNHL with extended latency of wave I in ABR. Collectively, these findings indicate that hearing impairment associated with impaired Schwann cell-mediated myelination at the peripheral segment of the cochlear nerve is a notable symptom of MD-DG.