De novo variants in GREB1L are associated with non-syndromic inner ear malformations and deafness.
De novo variants in GREB1L are associated with non-syndromic inner ear malformations and deafness.
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DOI：
10.1007/s00439-018-1898-8
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发表时间：
2018-07
期刊：
影响因子：
5.3
通讯作者：
Friedman RA
中科院分区：
文献类型：
--
作者：
Schrauwen I;Kari E;Mattox J;Llaci L;Smeeton J;Naymik M;Raible DW;Knowles JA;Crump JG;Huentelman MJ;Friedman RA
先天性内耳畸形同时影响骨迷路和膜迷路，可能对听力和语言发育产生破坏性影响。除了前庭水管扩大，非综合征性内耳畸形是罕见的，其潜在的分子生物学至今仍未充分研究。为了确定可能在内耳发育中起重要作用的分子因素，我们在患有严重内耳畸形的年轻无关受试者中采用了基于家族的三外显子组测序方法。我们在GREB 1 L中鉴定了两个先前未报道的从头功能丧失变体[c.4368G>T;p.（Glu1410fs）和c.982C>T;p.（Arg 328 *）]在两个受影响的受试者缺席耳蜗和第8颅神经畸形。这些受影响的受试者中的耳蜗发育不全表明在内耳发育的非常早期阶段存在发育停滞或问题，例如在耳窝形成期间。在此时间范围内，小鼠颅面Greb 11 RNA表达达到峰值（E8.5）。它也在E13-E16期间在发育中的内耳中达到峰值，之后在成年期下降。Greb 1 l在颅面发育中的关键功能也在基因敲除小鼠中得到了证明，这些小鼠会出现严重的颅面异常。此外，我们发现Greb 1 l −/−斑马鱼表现出异常感觉上皮神经支配的丧失。Greb 1 l在感觉上皮神经支配发育中的重要作用得到了在两个受影响受试者中观察到的第8脑神经缺陷的支持。总之，我们证明GREB 1 L是早期内耳和第8脑神经发育的关键球员。对耳蜗前庭解剖学的了解为人工耳蜗植入术提供了挑战。将分子诊断与成像技术相结合可能有助于未来个性化治疗干预的发展。
Congenital inner ear malformations affecting both the osseous and membranous labyrinth can have a devastating impact on hearing and language development. With the exception of an enlarged vestibular aqueduct, non-syndromic inner ear malformations are rare, and their underlying molecular biology has thus far remained understudied. To identify molecular factors that might be important in the developing inner ear, we adopted a family-based trio exome sequencing approach in young unrelated subjects with severe inner ear malformations. We identified two previously unreported de novo loss-of-function variants in GREB1L [c.4368G>T;p.(Glu1410fs) and c.982C>T;p.(Arg328*)] in two affected subjects with absent cochleae and 8th cranial nerve malformations. The cochlear aplasia in these affected subjects suggests that a developmental arrest or problem at a very early stage of inner ear development exists, e.g. during the otic pit formation. Craniofacial Greb1l RNA expression peaks in mice during this time-frame (E8.5). It also peaks in the developing inner ear during E13–E16, after which it decreases in adulthood. The crucial function of Greb1l in craniofacial development is also evidenced in knockout mice, which develop severe craniofacial abnormalities. In addition, we show that Greb1l−/− zebrafish exhibit a loss of abnormal sensory epithelia innervation. An important role for Greb1l in sensory epithelia innervation development is supported by the 8th cranial nerve deficiencies seen in both affected subjects. In conclusion, we demonstrate that GREB1L is a key player in early inner ear and 8th cranial nerve development. Abnormalities in cochleovestibular anatomy can provide challenges for cochlear implantation. Combining a molecular diagnosis with imaging techniques might aid the development of individually tailored therapeutic interventions in the future.
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影响因子：
4.3
作者：
Marques AH;O'Connor TG;Roth C;Susser E;Bjørke-Monsen AL
通讯作者：
Bjørke-Monsen AL
影响因子：
9.8
作者：
De Tomasi, Lara;David, Pierre;Jeanpierre, Cecile
通讯作者：
Jeanpierre, Cecile
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
3.3
作者：
Brophy, Patrick D.;Rasmussen, Maria;Manak, J. Robert
通讯作者：
Manak, J. Robert