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
Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850, USA.
Hum Mutat. 2009 Apr;30(4):599-608. doi: 10.1002/humu.20884.
Hearing loss with enlargement of the vestibular aqueduct (EVA) can be associated with mutations of the SLC26A4 gene encoding pendrin, a transmembrane Cl(-)/I(-)/HCO(3)(-) exchanger. Pendrin's critical transport substrates are thought to be I(-) in the thyroid gland and HCO(3)(-) 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(-)/HCO(3)(-) 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 HCO(3)(-) 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.
伴有前庭导水管扩大（EVA）的听力损失可能与编码pendrin（一种跨膜Cl⁻/I⁻/HCO₃⁻交换体）的SLC26A4基因突变有关。Pendrin的关键转运底物在甲状腺中被认为是I⁻，在内耳中是HCO₃⁻。我们之前报道双等位基因SLC26A4突变与Pendred综合征性EVA相关，而一个或零个突变等位基因与非综合征性EVA相关。一项研究提出非综合征性EVA与编码具有残余转运活性的pendrin的SLC26A4等位基因之间存在相关性。在此，我们描述了自我们首次报告39例患者以来确定的47例EVA患者的表型和SLC26A4基因型。我们试图确定我们86例患者全队列中每个变异体的致病潜力。我们评估了在COS - 7细胞中表达的11种错义pendrin产物的转运情况。靶向质膜的产物在非洲爪蟾卵母细胞中表达以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⁻/HCO₃⁻交换速率常数为野生型值的13%至93%。p.F335L、p.L597S、p.M775T和p.R776C通常在非综合征性EVA中作为单等位基因突变体被发现。p.L597S的高正常对照携带者率表明在这种情况下它是一个偶然检测到的非致病变异体。我们观察到功能减退变异体对HCO₃⁻与I⁻交换有中等程度的差异效应，但其程度不支持与非综合征性EVA存在因果关联。然而，这些等位基因在与Pendred综合征中的突变等位基因呈反式构型时可能具有致病性。
