Hypo-functional SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms?
Hypo-functional SLC26A4 variants associated with nonsyndromic hearing loss and enlargement of the vestibular aqueduct: genotype-phenotype correlation or coincidental polymorphisms?
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DOI：
10.1002/humu.20884
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发表时间：
2009-04
期刊：
影响因子：
3.9
通讯作者：
Griffith, Andrew J.
中科院分区：
文献类型：
--
作者：
Choi, Byung Yoon;Stewart, Andrew K.;Madeo, Anne C.;Pryor, Shannon P.;Lenhard, Suzanne;Kittles, Rick;Eisenman, David;Kim, H. Jeffrey;Niparko, John;Thomsen, James;Arnos, Kathleen S.;Nance, Walter E.;King, Kelly A.;Zalewski, Christopher K.;Brewer, Carmen C.;Shawker, Thomas;Reynolds, James C.;Butman, John A.;Karniski, Lawrence P.;Alper, Seth L.;Griffith, Andrew J.
关键词：
前庭导水管扩大（伊娃）引起的听力损失可能与编码pendrin（一种跨膜Cl−/I−/HCO 3 −交换蛋白）的SLC 26 A4基因突变有关。Pendrin的关键转运底物被认为是甲状腺中的I−和内耳中的HCO 3 −。我们以前报道过双等位基因SLC 26 A4突变与Pendred综合征型伊娃相关，而一个或零个突变等位基因与非综合征型伊娃相关。一项研究提出了非综合征性伊娃与编码pendrin的SLC 26 A4等位基因与残留转运活性的相关性。在这里，我们描述的表型和SLC 26 A4基因型的47例伊娃患者确定，因为我们的第一个报告的39例。我们试图在我们的86例患者的整个队列中确定每个变体的致病潜力。我们评估了在COS-7细胞中表达的11种错义pendrin产物的运输。在非洲爪蟾卵母细胞中表达靶向质膜的产物，用于测量阴离子交换活性。p.F335L、p.C565Y、p.L597S、p.M775T和p.R776C的Cl−/I−和Cl−/HCO 3 −交换速率常数范围为野生型值的13%至93%。p.F335 L、p.L597 S、p.M775 T和p.R776 C通常在非综合征型伊娃中作为单等位基因变体发现。p.L597S的高正常对照携带率表明，在这种情况下，它是一种偶然检测到的非致病性变体。我们观察到HCO 3-与I-交换时功能减退变异体的中度差异效应，但其幅度不支持与非综合征性伊娃的因果关系。然而，这些等位基因在Pendred综合征中与突变等位基因反式构型可能是致病的。
Hearing loss with enlargement of the vestibular aqueduct (EVA) can be associated with mutations of the SLC26A4 gene encoding pendrin, a transmembrane Cl−/I−/HCO3− exchanger. Pendrin’s critical transport substrates are thought to be I− in the thyroid gland and HCO3− in the inner ear. We previously reported that bi-allelic SLC26A4 mutations are associated with Pendred syndromic EVA whereas one or zero mutant alleles are associated with nonsyndromic EVA. One study proposed a correlation of nonsyndromic EVA with SLC26A4 alleles encoding pendrin with residual transport activity. Here we describe the phenotypes and SLC26A4 genotypes of 47 EVA patients ascertained since our first report of 39 patients. We sought to determine the pathogenic potential of each variant in our full cohort of 86 patients. We evaluated the trafficking of 11 missense pendrin products expressed in COS-7 cells. Products that targeted to the plasma membrane were expressed in Xenopus oocytes for measurement of anion exchange activity. p.F335L, p.C565Y, p.L597S, p.M775T, and p.R776C had Cl−/I− and Cl−/HCO3− exchange rate constants that ranged from 13 to 93% of wild type values. p.F335L, p.L597S, p.M775T and p.R776C are typically found as mono-allelic variants in nonsyndromic EVA. The high normal control carrier rate for p.L597S indicates it is a coincidentally detected nonpathogenic variant in this context. We observed moderate differential effects of hypo-functional variants upon exchange of HCO3− versus I− but their magnitude does not support a causal association with nonsyndromic EVA. However, these alleles could be pathogenic in trans configuration with a mutant allele in Pendred syndrome.
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影响因子：
5.5
作者：
Adler, Lior;Efrati, Edna;Zelikovic, Israel
通讯作者：
Zelikovic, Israel
影响因子：
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作者：
Lopez-Bigas, N;Melchionda, S;Estivill, X
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影响因子：
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DOI：
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发表时间：
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