Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis, in which spinal curvature develops in adolescence, and 90% of patients are female. Scoliosis is a debilitating disease that often requires bracing or surgery in severe cases. AIS affects 2%–5.2% of the population; however, the biological origin of the disease remains poorly understood. In this study, we aimed to determine the function of a highly conserved genomic region previously linked to AIS using a mouse model generated by CRISPR-CAS9 gene editing to knockout this area of the genome to understand better its contribution to AIS, which we named AIS_CRMΔ. We also investigated the upstream factors that regulate the activity of this enhancer in vivo, whether the spatial expression of the LBX1 protein would change with the loss of AIS-CRM function, and whether any phenotype would arise after deletion of this region. We found a significant increase in mRNA expression in the developing neural tube at E10.5, and E12.5, for not only Lbx1 but also other neighboring genes. Adult knockout mice showed vertebral rotation and proprioceptive deficits, also observed in human AIS patients. In conclusion, our study sheds light on the elusive biological origins of AIS, by targeting and investigating a highly conserved genomic region linked to AIS in humans. These findings provide valuable insights into the function of the investigated region and contribute to our understanding of the underlying causes of this debilitating disease.

中文翻译：

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删除与青少年特发性脊柱侧凸相关的保守基因组区域会导致小鼠椎骨旋转

青少年特发性脊柱侧凸（AIS）是最常见的脊柱侧凸形式，脊柱在青春期发生弯曲，90%的患者是女性。脊柱侧弯是一种使人衰弱的疾病，严重时通常需要支具或手术。 AIS 影响 2%–5.2% 的人口；然而，对该疾病的生物学起源仍知之甚少。在本研究中，我们旨在确定先前与 AIS 相关的高度保守的基因组区域的功能，使用 CRISPR-CAS9 基因编辑生成的小鼠模型来敲除基因组的该区域，以更好地了解其对 AIS 的贡献，我们将其命名为 AIS_CRMΔ 。我们还研究了体内调节该增强子活性的上游因素，LBX1蛋白的空间表达是否会随着AIS-CRM功能的丧失而改变，以及删除该区域后是否会出现任何表型。我们发现发育中的神经管中 E10.5 和 E12.5 的 mRNA 表达显着增加，不仅包括 Lbx1，还包括其他邻近基因。成年基因敲除小鼠表现出椎骨旋转和本体感觉缺陷，这在人类 AIS 患者中也观察到。总之，我们的研究通过针对和研究与人类 AIS 相关的高度保守的基因组区域，揭示了 AIS 难以捉摸的生物学起源。这些发现为研究区域的功能提供了宝贵的见解，并有助于我们了解这种使人衰弱的疾病的根本原因。