Genotype-phenotype correlation in DFNB8/10 families with TMPRSS3 mutations.
Genotype-phenotype correlation in DFNB8/10 families with TMPRSS3 mutations.
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DOI：
10.1007/s10162-011-0282-3
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发表时间：
2011-12
影响因子：
2.4
通讯作者：
Kunst, Henricus P. M.
中科院分区：
文献类型：
--
作者：
Weegerink, Nicole J. D.;Schraders, Margit;Oostrik, Jaap;Huygen, Patrick L. M.;Strom, Tim M.;Granneman, Susanne;Pennings, Ronald J. E.;Venselaar, Hanka;Hoefsloot, Lies H.;Elting, Mariet;Cremers, Cor W. R. J.;Admiraal, Ronald J. C.;Kremer, Hannie;Kunst, Henricus P. M.
关键词：
在本研究中，研究了 8 个具有 TMPRSS3 复合杂合突变的荷兰 DFNB8/10 家族的基因型-表型相关性。我们通过关注突变数据来比较各家族的表型。目前家族中 TMPRSS3 基因的复合杂合变异体包括一种新变异体 p.Val199Met 和四种先前描述的致病变异体：p.Ala306Thr、p.Thr70fs、p.Ala138Glu 和 p.Cys107Xfs。此外，之前曾报道过可能存在多态性的p.Ala426Thr变体也在一个家族中被发现。所有受影响的家庭成员均报告进行性双侧听力障碍，发病年龄和进展速度各不相同。一般来说，听力障碍首先影响高频，根据突变，低频迟早会开始恶化，最终导致听力图配置平坦。滑雪坡听力图配置暗示 TMPRSS3 的参与。我们的数据表明，不仅蛋白质截短突变 p.T70fs 具有严重影响，而且氨基酸取代 p.Ala306Thr 和 p.Val199Met 也具有严重影响。这三种突变中的两种的组合会导致语前严重听力障碍。然而，与 p.Ala426Thr 或 p.Ala138Glu 突变相结合，可以看到较温和的表型，伴有舌后听力障碍的发作。因此，后一种突变对蛋白质功能的损害可能较小。需要进一步的研究来区分不同 TMPRSS3 突变之间可能的表型差异。对植入人工耳蜗的患者的性能评估表明，对于 TMPRSS3 突变的患者来说，这是一个很好的治疗选择，因为植入后达到了令人满意的言语接受能力。本文的在线版本 (doi:10.1007/s10162-011-0282-3) 包含补充材料，可供授权用户使用。
In the present study, genotype–phenotype correlations in eight Dutch DFNB8/10 families with compound heterozygous mutations in TMPRSS3 were addressed. We compared the phenotypes of the families by focusing on the mutation data. The compound heterozygous variants in the TMPRSS3 gene in the present families included one novel variant, p.Val199Met, and four previously described pathogenic variants, p.Ala306Thr, p.Thr70fs, p.Ala138Glu, and p.Cys107Xfs. In addition, the p.Ala426Thr variant, which had previously been reported as a possible polymorphism, was found in one family. All affected family members reported progressive bilateral hearing impairment, with variable onset ages and progression rates. In general, the hearing impairment affected the high frequencies first, and sooner or later, depending on the mutation, the low frequencies started to deteriorate, which eventually resulted in a flat audiogram configuration. The ski-slope audiogram configuration is suggestive for the involvement of TMPRSS3. Our data suggest that not only the protein truncating mutation p.T70fs has a severe effect but also the amino acid substitutions p.Ala306Thr and p.Val199Met. A combination of two of these three mutations causes prelingual profound hearing impairment. However, in combination with the p.Ala426Thr or p.Ala138Glu mutations, a milder phenotype with postlingual onset of the hearing impairment is seen. Therefore, the latter mutations are likely to be less detrimental for protein function. Further studies are needed to distinguish possible phenotypic differences between different TMPRSS3 mutations. Evaluation of performance of patients with a cochlear implant indicated that this is a good treatment option for patients with TMPRSS3 mutations as satisfactory speech reception was reached after implantation. The online version of this article (doi:10.1007/s10162-011-0282-3) contains supplementary material, which is available to authorized users.
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