Department of Epigenetics and Molecular Carcinogenesis, Science Park, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Int J Mol Sci. 2020 Nov 24;21(23):8922. doi: 10.3390/ijms21238922.
The gene was initially discovered as a putative tumor suppressor. More recently, its association with multiple central nervous system (CNS) pathologies has been recognized. biallelic germline pathogenic variants have been implicated in spinocerebellar ataxia type 12 (SCAR12; MIM:614322) and in early infantile epileptic encephalopathy (EIEE28; MIM:616211). germline copy number variants have also been associated with autism spectrum disorder (ASD). All identified germline genomic variants lead to partial or complete loss of WWOX function. Importantly, large-scale genome-wide association studies have also identified as a risk gene for common neurodegenerative conditions such as Alzheimer's disease (AD) and multiple sclerosis (MS). Thus, the spectrum of CNS disorders associated with WWOX is broad and heterogeneous, and there is little understanding of potential mechanisms at play. Exploration of gene expression databases indicates that expression is comparatively higher in the human cerebellar cortex than in other CNS structures. However, RNA in-situ hybridization data from the Allen Mouse Brain Atlas show that specific regions of the basolateral amygdala (BLA), the medial entorhinal cortex (EC), and deep layers of the isocortex can be singled out as brain regions with specific higher levels of expression. These observations are in close agreement with single-cell RNA-seq data which indicate that neurons from the medial entorhinal cortex, Layer 5 from the frontal cortex as well as GABAergic basket cells and granule cells from cerebellar cortex are the specific neuronal subtypes that display the highest expression levels. Importantly, the brain regions and cell types in which WWOX is most abundantly expressed, such as the EC and BLA, are intimately linked to pathologies and syndromic conditions in turn associated with this gene, such as epilepsy, intellectual disability, ASD, and AD. Higher expression in interneurons and granule cells from cerebellum points to a direct link to the described cerebellar ataxia in cases of WWOX loss of function. We now know that total or partial impairment of WWOX function results in a wide and heterogeneous variety of neurodegenerative conditions for which the specific molecular mechanisms remain to be deciphered. Nevertheless, these observations indicate an important functional role for WWOX in normal development and function of the CNS. Evidence also indicates that disruption of WWOX expression at the gene or protein level in CNS has significant deleterious consequences.
该基因最初被发现是一种潜在的肿瘤抑制因子。最近，人们认识到它与多种中枢神经系统（CNS）疾病有关。种系双等位基因突变与脊髓小脑性共济失调 12 型（SCAR12；MIM：614322）和早发性婴儿癫痫性脑病（EIEE28；MIM：616211）有关。种系拷贝数变异也与自闭症谱系障碍（ASD）有关。所有鉴定的种系基因组变异导致 WWOX 功能部分或完全丧失。重要的是，大规模全基因组关联研究还将 鉴定为常见神经退行性疾病（如阿尔茨海默病（AD）和多发性硬化症（MS））的风险基因。因此，与 WWOX 相关的 CNS 疾病谱广泛且异质，对潜在机制的了解甚少。对基因表达数据库的探索表明，与其他中枢神经系统结构相比， 在人类小脑皮层中的表达相对较高。然而，Allen 小鼠脑图谱的 RNA 原位杂交数据显示，外侧杏仁核（BLA）的特定区域、内侧内嗅皮层（EC）和大脑皮层的深层可以被单独挑出作为具有特定较高表达水平的脑区。这些观察结果与单细胞 RNA-seq 数据非常吻合，该数据表明，来自内侧内嗅皮层的神经元、来自前额皮层的第 5 层以及小脑皮层的 GABA 能 basket 细胞和颗粒细胞是显示最高 表达水平的特定神经元亚型。重要的是，在 WWOX 表达最丰富的脑区和细胞类型中，如 EC 和 BLA，与该基因相关的病理学和综合征条件密切相关，例如癫痫、智力障碍、ASD 和 AD。小脑颗粒细胞和中间神经元中 表达水平升高，表明在 WWOX 功能丧失的情况下，与描述的小脑共济失调有直接联系。现在我们知道，WWOX 功能的完全或部分损害会导致广泛而异质的神经退行性疾病，其具体分子机制仍有待破译。然而，这些观察结果表明 WWOX 在中枢神经系统的正常发育和功能中具有重要的功能作用。有证据表明，CNS 中 WWox 基因或蛋白表达的中断会产生严重的有害后果。
