Disruption of the ATE1 and SLC12A1 Genes by Balanced Translocation in a Boy with Non-Syndromic Hearing Loss
Disruption of the ATE1 and SLC12A1 Genes by Balanced Translocation in a Boy with Non-Syndromic Hearing Loss
复制标题
DOI：
10.1159/000355443
复制
发表时间：
2013-10
影响因子：
1.1
通讯作者：
B. Vona;C. Neuner;N. El Hajj;E. Schneider;R. Farcas;V. Beyer;U. Zechner;A. Keilmann;M. Poot;O. Bartsch;I. Nanda;T. Haaf
中科院分区：
文献类型：
--
作者：
B. Vona;C. Neuner;N. El Hajj;E. Schneider;R. Farcas;V. Beyer;U. Zechner;A. Keilmann;M. Poot;O. Bartsch;I. Nanda;T. Haaf
我们报告了一个非综合征性听力损失的男孩和一个明显的平衡易位t（10;15）（q26.13;q21.1）。在听力正常的兄弟、父亲和祖父中也发现了同样的易位;然而，这并不排除它参与疾病的发病机制，例如，通过揭示第二个突变。断裂点分析，通过FISH与BAC克隆和远程PCR产物揭示了一个破坏的乙酰转移酶1（ATE 1）基因易位染色体10和溶质载体家族12，成员1基因（SLC 12 A1）易位染色体15。SNP阵列分析显示受影响儿童的染色体区域既没有丢失也没有获得，并且由130个已知耳聋基因组成的靶向基因富集小组对致病性突变呈阴性。斑马鱼和人类的表达模式没有提供ATE 1和SLC 12 A1基因耳朵特异性功能的证据。男孩和180名GJB 2突变阴性的听力受损个体的2个基因的桑格测序未检测到纯合或复合杂合致病突变。我们的研究表明，在解开异质性表型的分子原因的许多困难。我们不能直接将ATE 1和/或SLC 12 A1的破坏与异常听力表型联系起来;然而，这些基因的突变可能在多基因或多因素形式的听力障碍中起作用。另一方面，我们的病人可能携带了一种致病突变，这种突变存在于一种迄今为止尚未发现的耳聋基因中。显然，单独破坏ATE 1和/或SLC 12 A1基因功能不会产生不良影响。
We report on a boy with non-syndromic hearing loss and an apparently balanced translocation t(10;15)(q26.13;q21.1). The same translocation was found in the normally hearing brother, father and paternal grandfather; however, this does not exclude its involvement in disease pathogenesis, for example, by unmasking a second mutation. Breakpoint analysis via FISH with BAC clones and long-range PCR products revealed a disruption of the arginyltransferase 1 (ATE1) gene on translocation chromosome 10 and the solute carrier family 12, member 1 gene (SLC12A1) on translocation chromosome 15. SNP array analysis revealed neither loss nor gain of chromosomal regions in the affected child, and a targeted gene enrichment panel consisting of 130 known deafness genes was negative for pathogenic mutations. The expression patterns in zebrafish and humans did not provide evidence for ear-specific functions of the ATE1 and SLC12A1 genes. Sanger sequencing of the 2 genes in the boy and 180 GJB2 mutation-negative hearing-impaired individuals did not detect homozygous or compound heterozygous pathogenic mutations. Our study demonstrates the many difficulties in unraveling the molecular causes of a heterogeneous phenotype. We cannot directly implicate disruption of ATE1 and/or SLC12A1 to the abnormal hearing phenotype; however, mutations in these genes may have a role in polygenic or multifactorial forms of hearing impairment. On the other hand, it is conceivable that our patient carries a disease-causing mutation in a so far unidentified deafness gene. Evidently, disruption of ATE1 and/or SLC12A1 gene function alone does not have adverse effects.