Scott-Hewitt Nicole J, Folts Christopher J, Hogestyn Jessica M, Piester Gavin, Mayer-Pröschel Margot, Noble Mark D
Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Department of Biochemistry, University of Rochester, Rochester, NY 14642, USA.
Hum Mol Genet. 2017 Aug 1;26(15):2825-2837. doi: 10.1093/hmg/ddx153.
Genome-wide association studies are identifying multiple genetic risk factors for several diseases, but the functional role of these changes remains mostly unknown. Variants in the galactocerebrosidase (GALC) gene, for example, were identified as a risk factor for Multiple Sclerosis (MS); however, the potential biological relevance of GALC variants to MS remains elusive. We found that heterozygote GALC mutant mice have reduced myelin debris clearance and diminished remyelination after a demyelinating insult. We found no histological or behavioral differences between adult wild-type and GALC +/- animals under normal conditions. Following exposure to the demyelinating agent cuprizone, however, GALC +/- animals had significantly reduced remyelination during recovery. In addition, the microglial phagocytic response and elevation of Trem2, both necessary for clearing damaged myelin, were markedly reduced in GALC +/- animals. These altered responses could be corrected in vitro by treatment with NKH-477, a compound discovered as protective in our previous studies on Krabbe disease, which is caused by mutations in both GALC alleles. Our data are the first to show remyelination defects in individuals with a single mutant GALC allele, suggesting such carriers may have increased vulnerability to myelin damage following injury or disease due to inefficient myelin debris clearance. We thus provide a potential functional link between GALC variants and increased MS susceptibility, particularly due to the failure of remyelination associated with progressive MS. Finally, this work demonstrates that genetic variants identified through genome-wide association studies may contribute significantly to complex diseases, not by driving initial symptoms, but by altering repair mechanisms.
全基因组关联研究正在识别多种疾病的多个遗传风险因素，但这些变化的功能作用大多仍不为人知。例如，半乳糖脑苷脂酶（GALC）基因的变异被确定为多发性硬化症（MS）的一个风险因素；然而，GALC变异与MS的潜在生物学相关性仍然难以捉摸。我们发现，杂合子GALC突变小鼠在脱髓鞘损伤后髓鞘碎片清除减少，髓鞘再生减弱。我们发现在正常条件下，成年野生型和GALC +/- 动物之间没有组织学或行为上的差异。然而，在接触脱髓鞘剂铜螯合剂后，GALC +/- 动物在恢复过程中的髓鞘再生明显减少。此外，GALC +/- 动物中，清除受损髓鞘所必需的小胶质细胞吞噬反应和Trem2升高均明显降低。用NKH-477处理可在体外纠正这些改变的反应，NKH-477是我们之前对由两个GALC等位基因突变引起的克拉伯病的研究中发现具有保护作用的一种化合物。我们的数据首次表明，具有单个GALC突变等位基因的个体存在髓鞘再生缺陷，这表明此类携带者可能由于髓鞘碎片清除效率低下，在受伤或患病后更容易受到髓鞘损伤。因此，我们提供了GALC变异与MS易感性增加之间的潜在功能联系，特别是由于与进展性MS相关的髓鞘再生失败。最后，这项工作表明，通过全基因组关联研究确定的遗传变异可能对复杂疾病有重大影响，不是通过引发初始症状，而是通过改变修复机制。
