A novel missense variant in MYO3A is associated with autosomal dominant high-frequency hearing loss in a German family
A novel missense variant in MYO3A is associated with autosomal dominant high-frequency hearing loss in a German family
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DOI：
10.1002/mgg3.1343
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发表时间：
2020-06-10
影响因子：
2
通讯作者：
Vona, Barbara
中科院分区：
文献类型：
--
作者：
Doll, Julia;Hofrichter, Michaela A. H.;Vona, Barbara
MYO3A编码肌球蛋白IIIA蛋白，与常染色体隐性遗传和常染色体显性遗传的非综合征性听力损失相关。到目前为止，只有两个位于MYO3A的马达头域的错义变体已被描述在常染色体显性遗传的进行性，轻度至重度感音神经性听力损失的家庭。这些变体改变肌球蛋白IIIA.Methods的ATP酶活性的先证者从一个三代的德国家庭与语前，中度到深度，高频听力损失的外显子组测序进行。分离分析证实了显性遗传模式。结果发现一种新的杂合错义突变体c.716T>C，p. MYO3A的激酶结构域中的Leu239Pro被鉴定为计算机模拟预测为致病的。结论纯音听阈的相关分析显示听力损失是进行性的，尤其是高频听力损失。在本研究中，我们报告了第一个显性可能致病变异MYO3A在欧洲家庭和进一步支持MYO3A作为一个常染色体显性遗传性听力损失基因。
Background MYO3A, encoding the myosin IIIA protein, is associated with autosomal recessive and autosomal dominant nonsyndromic hearing loss. To date, only two missense variants located in the motor-head domain of MYO3A have been described in autosomal dominant families with progressive, mild-to-profound sensorineural hearing loss. These variants alter the ATPase activity of myosin IIIA.Methods Exome sequencing of a proband from a three-generation German family with prelingual, moderate-to-profound, high-frequency hearing loss was performed. Segregation analysis confirmed a dominant inheritance pattern. Regression analysis of mean hearing level thresholds per individual and ear was performed at high-, mid-, and low-frequencies.Results A novel heterozygous missense variant c.716T>C, p.(Leu239Pro) in the kinase domain of MYO3A was identified that is predicted in silico as disease causing. High-frequency, progressive hearing loss was identified.Conclusion Correlation analysis of pure-tone hearing thresholds revealed progressive hearing loss, especially in the high-frequencies. In the present study, we report the first dominant likely pathogenic variant in MYO3A in a European family and further support MYO3A as an autosomal dominant hearing loss gene.