Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY 11568, USA.
Hum Mol Genet. 2022 Dec 16;31(24):4207-4216. doi: 10.1093/hmg/ddac172.
Kallmann syndrome (KS) is a congenital disorder characterized by idiopathic hypogonadotropic hypogonadism and olfactory dysfunction. KS is linked to variants in >34 genes, which are scattered across the human genome and show disparate biological functions. Although the genetic basis of KS is well studied, the mechanisms by which disruptions of these diverse genes cause the same outcome of KS are not fully understood. Here we show that disruptions of KS-linked genes affect the same biological processes, indicating convergent molecular mechanisms underlying KS. We carried out machine learning-based predictions and found that KS-linked mutations in heparan sulfate 6-O-sulfotransferase 1 (HS6ST1) are likely loss-of-function mutations. We next disrupted Hs6st1 and another KS-linked gene, fibroblast growth factor receptor 1 (Fgfr1), in mouse neuronal cells and measured transcriptome changes using RNA sequencing. We found that disruptions of Hs6st1 and Fgfr1 altered genes in the same biological processes, including the upregulation of genes in extracellular pathways and the downregulation of genes in chromatin pathways. Moreover, we performed genomics and bioinformatics analyses and found that Hs6st1 and Fgfr1 regulate gene transcription likely via the transcription factor Sox9/Sox10 and the chromatin regulator Chd7, which are also associated with KS. Together, our results demonstrate how different KS-linked genes work coordinately in a convergent signaling pathway to regulate the same biological processes, thus providing new insights into KS.
卡尔曼综合征（KS）是一种先天性疾病，其特征为特发性促性腺激素低下性性腺功能减退症和嗅觉功能障碍。KS 与超过 34 个基因的变异有关，这些基因分布在人类基因组中，具有不同的生物学功能。尽管 KS 的遗传基础已经得到了很好的研究，但这些不同基因的突变导致 KS 的相同结果的机制仍不完全清楚。在这里，我们表明，KS 相关基因的突变会影响相同的生物学过程，这表明 KS 存在共同的分子机制。我们进行了基于机器学习的预测，发现硫酸乙酰肝素 6-O-磺基转移酶 1（HS6ST1）中的 KS 相关突变很可能是功能丧失突变。接下来，我们在小鼠神经元细胞中破坏了 Hs6st1 和另一个 KS 相关基因成纤维细胞生长因子受体 1（Fgfr1），并使用 RNA 测序测量了转录组变化。我们发现，Hs6st1 和 Fgfr1 的破坏改变了相同的生物学过程中的基因，包括细胞外途径中的基因上调和染色质途径中的基因下调。此外，我们进行了基因组学和生物信息学分析，发现 Hs6st1 和 Fgfr1 可能通过转录因子 Sox9/Sox10 和染色质调节剂 Chd7 来调节基因转录，这些因子也与 KS 有关。总之，我们的结果表明，不同的 KS 相关基因如何在一个集中的信号通路中协同工作，从而调节相同的生物学过程，为 KS 提供了新的见解。
