Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere's disease
Identification of two novel mutations in FAM136A and DTNA genes in autosomal-dominant familial Meniere's disease
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DOI：
10.1093/hmg/ddu524
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发表时间：
2015-02-15
影响因子：
3.5
通讯作者：
Lopez-Escamez, Jose A.
中科院分区：
文献类型：
--
作者：
Requena, Teresa;Cabrera, Sonia;Lopez-Escamez, Jose A.
梅尼埃病（MD）是一种慢性内耳疾病，定义为感音神经性听力损失，耳鸣和阵发性眩晕，家族性MD在5-15%的散发病例中观察到。虽然其病理生理学在很大程度上是未知的，在人类颞骨的研究发现内淋巴在耳蜗中阶的积累。通过全外显子组测序，我们在FAM 136 A和DTNA基因中发现了两种新型杂合单核苷酸变体，这两种变体都存在于一个连续几代有三例受影响病例的西班牙家庭中，高度提示为常染色体显性遗传。FAM 136 A基因中的无义突变导致终止密码子破坏FAM 136 A蛋白产物。测序结果显示，患者淋巴母细胞中有两个FAM 136 A的mRNA转录本，免疫印迹法证实了这一点。携带FAM 136 A突变的人在淋巴母细胞系中两种转录本的表达水平均显著降低。DTNA基因中的错义突变产生了一个新的剪接位点，其跳过外显子21并导致较短的选择性转录。我们还表明，FAM 136 A和DTNA蛋白表达的神经感觉上皮的壶腹嵴的大鼠通过免疫组织化学。虽然FAM 136 A编码一种功能未知的线粒体蛋白，但DTNA编码一种参与突触形成和稳定的细胞因子相互作用膜蛋白，在血脑屏障的通透性中起关键作用。这两个基因都没有在听力损失患者中描述，FAM 136 A和DTNA是常见MD的候选基因。
Meniere's disease (MD) is a chronic disorder of the inner ear defined by sensorineural hearing loss, tinnitus and episodic vertigo, and familial MD is observed in 5-15% of sporadic cases. Although its pathophysiology is largely unknown, studies in human temporal bones have found an accumulation of endolymph in the scala media of the cochlea. By whole-exome sequencing, we have identified two novel heterozygous single-nucleotide variants in FAM136A and DTNA genes, both in a Spanish family with three affected cases in consecutive generations, highly suggestive of autosomal-dominant inheritance. The nonsense mutation in the FAM136A gene leads to a stop codon that disrupts the FAM136A protein product. Sequencing revealed two mRNA transcripts of FAM136A in lymphoblasts from patients, which were confirmed by immunoblotting. Carriers of the FAM136A mutation showed a significant decrease in the expression level of both transcripts in lymphoblastoid cell lines. The missense mutation in the DTNA gene produces a novel splice site which skips exon 21 and leads to a shorter alternative transcript. We also demonstrated that FAM136A and DTNA proteins are expressed in the neurosensorial epithelium of the crista ampullaris of the rat by immunohistochemistry. While FAM136A encodes a mitochondrial protein with unknown function, DTNA encodes a cytoskeleton-interacting membrane protein involved in the formation and stability of synapses with a crucial role in the permeability of the blood-brain barrier. Neither of these genes has been described in patients with hearing loss, FAM136A and DTNA being candidate gene for familiar MD.