Girotto Giorgia, Scheffer Déborah I, Morgan Anna, Vozzi Diego, Rubinato Elisa, Di Stazio Mariateresa, Muzzi Enrico, Pensiero Stefano, Giersch Anne B, Corey David P, Gasparini Paolo
University of Trieste-Department of Medical, Surgical and Health Sciences, Trieste, Italy.
Harvard Medical School-Howard Hughes Medical Institute, Department of Neurobiology, Boston MA, United States.
Sci Rep. 2015 Dec 22;5:18568. doi: 10.1038/srep18568.
Hereditary Hearing Loss (HHL) is an extremely heterogeneous disorder. Approximately 30 out of 80 known HHL genes are associated with autosomal dominant forms. Here, we identified PSIP1/LEDGF (isoform p75) as a novel strong candidate gene involved in dominant HHL. Using exome sequencing we found a frameshift deletion (c.1554_1555del leading to p.E518Dfs*2) in an Italian pedigree affected by sensorineural mild-to-moderate HHL but also showing a variable eye phenotype (i.e. uveitis, optic neuropathy). This deletion led to a premature stop codon (p.T519X) with truncation of the last 12 amino acids. PSIP1 was recently described as a transcriptional co-activator regulated by miR-135b in vestibular hair cells of the mouse inner ear as well as a possible protector against photoreceptor degeneration. Here, we demonstrate that it is ubiquitously expressed in the mouse inner ear. The PSIP1 mutation is associated with a peculiar audiometric slope toward the high frequencies. These findings indicate that PSIP1 likely plays an important role in HHL.
遗传性听力损失（HHL）是一种极其异质性的疾病。在已知的80个HHL基因中，约有30个与常染色体显性遗传形式相关。在此，我们确定PSIP1/LEDGF（异构体p75）是参与显性HHL的一个新的强候选基因。通过外显子组测序，我们在一个受感音神经性轻至中度HHL影响、但也表现出可变眼部表型（即葡萄膜炎、视神经病变）的意大利家系中发现了一个移码缺失（c.1554_1555del，导致p.E518Dfs*2）。该缺失导致了一个提前终止密码子（p.T519X），并使最后12个氨基酸截短。PSIP1最近被描述为一种在小鼠内耳前庭毛细胞中受miR-135b调控的转录共激活因子，以及一种可能预防光感受器退化的因子。在此，我们证明它在小鼠内耳中普遍表达。PSIP1突变与高频方向的特殊听力图斜率相关。这些发现表明PSIP1可能在HHL中起重要作用。
