Convergent biological pathways underlying the Kallmann syndrome-linked genes Hs6st1 and Fgfr1

Abstract

Kallmann syndrome (KS) is a congenital disorder characterized by idiopathic hypogonadotropic hypogonadism and olfactory dysfunction. KS is linked to variants in more than 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.

Molecular mechanisms of hypothalamic-pituitary-ovarian/thyroid axis regulating age at first egg in geese

“…Lastly, FGFR1 , one of the first genes associated with Kallmann Syndrome, was known to be involved in the development and migration of GnRH neurons ( Boehm et al, 2015 ). Individuals with Kallmann Syndrome showed incomplete or absent puberty, infertility, low sex steroid levels, and low gonadotropin levels ( Moon and Zhao, 2022 ).…”

Variety of genetic defects in GnRH and hypothalamic–pituitary signaling and development in normosmic patients with IHH

“…Recently, a comprehensive functional study on KS-linked genes FGFR1 , HS6ST1 , SOX9/10 , and CHD7 was conducted. Using machine learning-based predictions and functional knock-outs, the authors evidenced convergence in signaling pathway and contribution to the same processes via various activities ( 59 ). Moreover, a significant burden is related to intronic changes since such variability is usually ignored due to a lack of convincing evidence (difficulties in estimation pathogenicity, limited access to algorithms predicting disruption of splice/regulatory sites, and their reliability).…”

Transcriptome and secretome profiling of sensory neurons reveals sex differences in pathways relevant to insulin sensing and insulin secretion

“…Raw sequence data (.bcl files) generated from Illumina HiSeq was converted into fastq files and de‐multiplexed using Illumina bcl2fastq 2.20 software. The RNA‐seq data analyses were performed as previously described 40,41 . Briefly, the FASTQ files were aligned to mouse mm10 genome using STAR 2.7.7a 42 with the following parameters: ‘–runThreadN 40 –outFilterMultimapNmax 1 –outFilterMismatchNmax 3 –outFilterScoreMinOverLread 0.25 –outFilterMatchNminOverLread 0.25’.…”

“…The RNA-seq data analyses were performed as previously described. 40,41 Briefly, the FASTQ files were aligned to mouse mm10 genome using STAR 2.7.7a 42 with the following parameters: '-runThreadN 40 -outFilterMultimapNmax 1 -outFilterMismatchNmax 3 -outFilterScoreMinOverLread 0.25 -outFilterMatchNminOverLread 0.25'. A Perl script was used to calculate the total number of mapped reads and the number of reads that aligned to the exons of each gene.…”