Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse.
Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse.
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DOI：
10.1371/journal.pgen.1007297
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发表时间：
2018-03
期刊：
影响因子：
4.5
通讯作者：
Riazuddin S
中科院分区：
文献类型：
--
作者：
Yousaf R;Gu C;Ahmed ZM;Khan SN;Friedman TB;Riazuddin S;Shears SB;Riazuddin S
常染色体隐性遗传性非综合征性耳聋是一种遗传异质性疾病。在此，我们报告了位于染色体5q13.2-q23.2上的一个严重到严重的感音神经性耳聋基因座DFNB100。外显子组浓缩和大规模平行测序显示，在两个明显不相关的巴基斯坦大家庭中，PPIP5K2的c.2510G>；转换变体与DFNB100相关的听力损失分离。PPIP5Ks酶相互转化5-IP7和IP8，这是焦磷酸肌醇(PP-IP)细胞信号家族的两个关键成员。它们在细胞信号和生物能量动态平衡的界面上的作用可以影响许多生物过程。据预测，在PPIP5K2的磷酸酶结构域中，c.2510G>；A转换变异体将用组氨酸(p.Arg837His)取代高度不变的精氨酸残基。生化研究表明，P.Arg837His变异体降低了PPIP5K2的磷酸酶活性，提高了其激酶活性。我们发现，在小鼠内耳，PPIP5K2表达于耳蜗毛细胞、前庭感觉毛细胞、支持细胞和螺旋神经节神经元。靶向缺失Ppi5k2磷酸酶结构域的纯合子小鼠表现出耳蜗外毛细胞退化和听力阈值提高。我们证明PPIP5K2在人类听力中具有作用，这表明PP-IP信号对于毛细胞的维持和内耳的功能是重要的。应用外显子测序和纯合性定位相结合的方法，在两个巴基斯坦血缘关系较大的家族中发现了位于DFNB100基因座的PPIP5K2错义突变[c.2510G>；A；p.(Arg837His)]，该突变与非综合征型、语前感音神经性耳聋相关。PPIP5K是调节焦磷酸肌醇(PP-IP)代谢的关键酶。生化分析表明，与野生型人PPIP5K2相比，PPIP5K2R837H变异体表现出较低的磷酸酶活性和较高的激酶活性，表明它促进了体内从5-IP7到IP8的代谢通量的增加。在啮齿动物内耳，PPIP5K2免疫反应阳性细胞位于耳蜗毛细胞、前庭毛细胞、支持细胞和螺旋神经节神经元。靶向缺失Ppi5k2磷酸酶结构域的纯合子小鼠表现为耳蜗外毛细胞变性和进行性听力损失。我们的工作首次描述了PPIP5K2的任何氨基酸变体，它既具有重要的功能，又与人类疾病有关。PPIP5K2的激酶/磷酸酶活性的无效循环使内耳功能特别容易受到PPIP5K2的磷酸酶活性的微小变化的影响。我们已经证明PPIP5K2的一个致病变异与人类的听力损失有关。因此，我们的观察赋予了PPIP5K2新的临床意义。
Autosomal recessive nonsyndromic hearing loss is a genetically heterogeneous disorder. Here, we report a severe-to-profound sensorineural hearing loss locus, DFNB100 on chromosome 5q13.2-q23.2. Exome enrichment followed by massive parallel sequencing revealed a c.2510G>A transition variant in PPIP5K2 that segregated with DFNB100-associated hearing loss in two large apparently unrelated Pakistani families. PPIP5Ks enzymes interconvert 5-IP7 and IP8, two key members of the inositol pyrophosphate (PP-IP) cell-signaling family. Their actions at the interface of cell signaling and bioenergetic homeostasis can impact many biological processes. The c.2510G>A transition variant is predicted to substitute a highly invariant arginine residue with histidine (p.Arg837His) in the phosphatase domain of PPIP5K2. Biochemical studies revealed that the p.Arg837His variant reduces the phosphatase activity of PPIP5K2 and elevates its kinase activity. We found that in mouse inner ear, PPIP5K2 is expressed in the cochlear and vestibular sensory hair cells, supporting cells and spiral ganglion neurons. Mice homozygous for a targeted deletion of the Ppip5k2 phosphatase domain exhibit degeneration of cochlear outer hair cells and elevated hearing thresholds. Our demonstration that PPIP5K2 has a role in hearing in humans indicates that PP-IP signaling is important to hair cell maintenance and function within inner ear. Exome sequencing coupled with homozygosity mapping was used to identify a missense variant [c.2510G>A; p.(Arg837His)] in PPIP5K2 at the DFNB100 locus that is associated with nonsyndromic, prelingual sensorineural deafness in two large consanguineous Pakistani families. PPIP5Ks are pivotal enzymes for regulating inositol pyrophosphate (PP-IP) turnover. Biochemical analyses revealed that, compared to wild type human PPIP5K2, the PPIP5K2R837H variant exhibited lower phosphatase activity and higher kinase activity, indicating that it promotes increased metabolic flux from 5-IP7 to IP8 in vivo. In rodent inner ears, PPIP5K2 immunoreactivity was observed in the cochlear and vestibular hair cells, supporting cells, and spiral ganglion neurons. Mouse mutants homozygous for the targeted deletion of Ppip5k2 phosphatase domain exhibit degeneration of cochlear outer hair cells and progressive hearing loss. Our work provides the first description of any amino acid variant of PPIP5K2 that is both functionally-significant and associates with a human disorder. The ‘futile cycling’ of the kinase/phosphatase activity of PPIP5K2 makes inner ear function particularly susceptible to even minor changes in the phosphatase activity of PPIP5K2. We have shown that a pathogenic variant in PPIP5K2 is associated with hearing loss in humans. Thus, PPIP5K2 is given new clinical significance by our observations.
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