Van der Hoeve’s syndrome, also known as osteogenesis imperfecta (OI), is a genetic connective tissue disorder characterized by fragile, fracture-prone bone and hearing loss. The disease is caused by a gene mutation in one of the two type I collagen genes COL1A1 or COL1A2. In this study, we identified a novel frameshift mutation of the COL1A1 gene (c.1607delG) in a family with OI using whole-exome sequencing, bioinformatics analysis and Sanger sequencing. This mutation may lead to the deletion of a portion of exon 23 and the generation of a premature stop codon in the COL1A1 gene. To further investigate the impact of this mutation, we established two induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells of OI patients carrying a novel mutation in the COL1A1 gene. Osteoblasts (OB) derived from OI-iPSCs exhibited reduced production of type I collagen and diminished ability to differentiate into osteoblasts. Using a CRISPR-based homology-directed repair strategy, we corrected the OI disease-causing COL1A1 novel mutations in iPSCs generated from an affected individual. Our results demonstrated that the diminished expression of type I collagen and osteogenic potential were enhanced in OB induced from corrected OI-iPSCs compared to those from OI-iPSCs. Overall, our results provide new insights into the genetic basis of Van der Hoeve’s syndrome and highlight the potential of iPSC technology for disease modeling and therapeutic development.

范德霍夫综合征，也称为成骨​​不全症 (OI)，是一种遗传性结缔组织疾病，其特征是骨质脆弱、易骨折和听力损失。该疾病是由两种 I 型胶原蛋白基因COL1A1或COL1A2之一的基因突变引起的。在本研究中，我们利用全外显子组测序、生物信息学分析和桑格测序，在 OI 家族中发现了COL1A1基因 (c.1607delG) 的新移码突变。该突变可能导致COL1A1基因中外显子 23 的部分缺失以及过早终止密码子的产生。为了进一步研究这种突变的影响，我们从携带COL1A1基因新突变的成骨不全患者的外周血单核细胞中建立了两个诱导多能干细胞 (iPSC) 系。来自 OI-iPSC 的成骨细胞 (OB) 表现出 I 型胶原蛋白产量减少和分化为成骨细胞的能力减弱。使用基于 CRISPR 的同源定向修复策略，我们纠正了受影响个体产生的 iPSC 中引起 OI 疾病的COL1A1新突变。我们的结果表明，与 OI-iPSC 相比，校正 OI-iPSC 诱导的 OB 中 I 型胶原表达减少，成骨潜力增强。总体而言，我们的结果为范德霍夫综合征的遗传基础提供了新的见解，并凸显了 iPSC 技术在疾病建模和治疗开发方面的潜力。