A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss.
A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss.
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PDE1C 基因的显性变异与非综合征性听力损失有关
DOI：
10.1007/s00439-018-1895-y
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发表时间：
2018-07
期刊：
影响因子：
5.3
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Wang L;Feng Y;Yan D;Qin L;Grati M;Mittal R;Li T;Sundhari AK;Liu Y;Chapagain P;Blanton SH;Liao S;Liu X
由于遗传异质性，鉴定具有导致非综合征性听力损失（NSHL）的变异的基因具有挑战性。过去，技术限制阻碍了全面的基因鉴定，这使得困难更加复杂。利用靶向捕获和下一代测序（NGS）的最新技术进步正在改变基因鉴定的面貌，并使快速且具有成本效益地对整个人类外显子组进行测序成为可能。在这里，我们描述了一个五代中国进行性，语后常染色体显性非综合征性听力损失（ADNSHL）的家庭。结合人群特异性突变芯片、靶向耳聋基因组、全外显子组测序（WES），我们确定PDE 1C（Phosphodiesterase 1C）c.958G T（p.A320S）为疾病相关变异。对p.A320S的结构建模见解强烈表明，序列改变可能会影响PDE 1C的底物结合口袋。通过对出生后第3天小鼠耳蜗的整体包埋免疫荧光，我们显示其在外毛细胞（OHC）和内毛细胞（IHC）胞质溶胶中的表达与溶酶体中的Lamp-1共定位。此外，我们提供的证据表明，该变体改变了环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP）的PDE 1C水解活性。总的来说，我们的研究结果表明，PDE 1C中的c.958G T变体可能会破坏Ca 2+稳态中cGMP信号传导和cAMP途径之间的串扰。
Identification of genes with variants causing non-syndromic hearing loss (NSHL) is challenging due to genetic heterogeneity. The difficulty is compounded by technical limitations that in the past prevented comprehensive gene identification. Recent advances in technology, using targeted capture and next-generation sequencing (NGS), is changing the face of gene identification and making it possible to rapidly and cost-effectively sequence the whole human exome. Here, we characterize a five-generation Chinese family with progressive, postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL). By combining population-specific mutation arrays, targeted deafness genes panel, whole exome sequencing (WES), we identified PDE1C (Phosphodiesterase 1C) c.958G>T (p.A320S) as the disease-associated variant. Structural modeling insights into p.A320S strongly suggest that the sequence alteration will likely affect the substrate-binding pocket of PDE1C. By whole-mount immunofluorescence on postnatal day 3 mouse cochlea, we show its expression in outer (OHC) and inner (IHC) hair cells cytosol co-localizing with Lamp-1 in lysosomes. Furthermore, we provide evidence that the variant alters the PDE1C hydrolytic activity for both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Collectively, our findings indicate that the c.958G>T variant in PDE1C may disrupt the cross talk between cGMP-signaling and cAMP pathways in Ca2+ homeostasis.
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DOI：
10.1073/pnas.1222295110
发表时间：
2013-04-30
影响因子：
11.1
作者：
Housley, Gary D.;Morton-Jones, Rachel;Ryan, Allen F.
通讯作者：
Ryan, Allen F.
DOI：
10.1007/978-3-642-17969-3_15
发表时间：
2011-01-01
期刊：
PHOSPHODIESTERASES AS DRUG TARGETS
影响因子：
--
作者：
Bjorgo, Elisa;Moltu, Kristine;Tasken, Kjetil
通讯作者：
Tasken, Kjetil
影响因子：
64.8
作者：
KURAHASHI, T;YAU, KW
通讯作者：
YAU, KW
影响因子：
64.8
作者：
LOWE, G;GOLD, GH
通讯作者：
GOLD, GH
影响因子：
37.8
作者：
Giannetta, Elisa;Isidori, Andrea M.;Lenzi, Andrea
通讯作者：
Lenzi, Andrea