Homozygous disruption of PDZD7 by reciprocal translocation in a consanguineous family: a new member of the Usher syndrome protein interactome causing congenital hearing impairment
Homozygous disruption of PDZD7 by reciprocal translocation in a consanguineous family: a new member of the Usher syndrome protein interactome causing congenital hearing impairment
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DOI：
10.1093/hmg/ddn395
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发表时间：
2009-02-15
影响因子：
3.5
通讯作者：
Haaf, Thomas
中科院分区：
文献类型：
--
作者：
Schneider, Eberhard;Maerker, Tina;Haaf, Thomas
在一名患有非综合征性先天性感音神经性听力障碍的男孩中检测到纯合相互易位 46,XY,t(10;11),t(10;11)。父母和他们的其他四个孩子都是杂合易位携带者，分别为46,XX,t(10;11)和46,XY,t(10;11)。使用区域特异性克隆与患者染色体的荧光原位杂交来定位染色体 10q24.3 上的细菌人工染色体 (BAC) RP11-108L7 内和染色体 11q23.3 上的 BAC CTD-2527F12 内的断点。通过载体连接克隆连接片段并测序。在含有 7 (PDZD7) 基因的 PDZ 结构域内鉴定出 10 号染色体断点，破坏了转录本 PDZD7-C（无 PDZ 结构域）的开放阅读框和转录本 PDZD7-D（具有 1 个 PDZ 和 2 个富含脯氨酸的结构域）的 5'-非翻译区。 11 号染色体断点位于基因间片段中。逆转录酶-聚合酶链反应分析揭示了人内耳中的 PDZD7 表达。已知在结构上与人类 PDZD7-D 最相似的鼠 Pdzd7 转录物在成人内耳和视网膜中表达。 PDZD7 与包含 PDZ 结构域的基因 USH1C（harmonin）和 DFNB31（whirlin）具有序列同源性。 Harmonin 和 Whirlin 的等位基因突变可导致 Usher 综合征（分别为 USH1C 和 USH2D）和先天性听力障碍（分别为 DFNB18 和 DFNB31）。蛋白质-蛋白质相互作用测定揭示了 PDZD7 在与人类 Usher 综合征相关的蛋白质网络中的整合。总的来说，我们的数据提供了强有力的证据，证明 PDZD7 是一种新的常染色体隐性耳聋致病基因，也是 Usher 综合征的主要候选基因。
A homozygous reciprocal translocation, 46,XY,t(10;11),t(10;11), was detected in a boy with non-syndromic congenital sensorineural hearing impairment. Both parents and their four other children were heterozygous translocation carriers, 46,XX,t(10;11) and 46,XY,t(10;11), respectively. Fluorescence in situ hybridization of region-specific clones to patient chromosomes was used to localize the breakpoints within bacterial artificial chromosome (BAC) RP11-108L7 on chromosome 10q24.3 and within BAC CTD-2527F12 on chromosome 11q23.3. Junction fragments were cloned by vector ligation and sequenced. The chromosome 10 breakpoint was identified within the PDZ domain containing 7 (PDZD7) gene, disrupting the open reading frame of transcript PDZD7-C (without PDZ domain) and the 5'-untranslated region of transcript PDZD7-D (with one PDZ and two prolin-rich domains). The chromosome 11 breakpoint was localized in an intergenic segment. Reverse transcriptase-polymerase chain reaction analysis revealed PDZD7 expression in the human inner ear. A murine Pdzd7 transcript that is most similar in structure to human PDZD7-D is known to be expressed in the adult inner ear and retina. PDZD7 shares sequence homology with the PDZ domain-containing genes, USH1C (harmonin) and DFNB31 (whirlin). Allelic mutations in harmonin and whirlin can cause both Usher syndrome (USH1C and USH2D, respectively) and congenital hearing impairment (DFNB18 and DFNB31, respectively). Protein-protein interaction assays revealed the integration of PDZD7 in the protein network related to the human Usher syndrome. Collectively, our data provide strong evidence that PDZD7 is a new autosomal-recessive deafness-causing gene and also a prime candidate gene for Usher syndrome.