Convergent biological pathways underlying the Kallmann syndrome-linked genes Hs6st1 and Fgfr1
Title
Convergent biological pathways underlying the Kallmann syndrome-linked genes Hs6st1 and Fgfr1
Date
2022
Publisher
Oxford University Press
Subject
Animals
Chromatin
EC 2.7.10.1
EC 2.8.2.
Hypogonadism genetics
Index Medicus
Kallmann Syndrome genetics metabolism
Mice
Mutation
Receptor
Fibroblast Growth Factor
Type 1 genetics
Sulfotransferases genetics
Chromatin
EC 2.7.10.1
EC 2.8.2.
Hypogonadism genetics
Index Medicus
Kallmann Syndrome genetics metabolism
Mice
Mutation
Receptor
Fibroblast Growth Factor
Type 1 genetics
Sulfotransferases genetics
Language
English
Abstract
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.
Source
Human Molecular Genetics, Volume 31, Issue 24, December 2022, pages 4207-4216
Rights
© The Author(s) 2022. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Format
PDF
Type
Text
Identifier
Bibliographic Citation
Moon, S., & Zhao, Y.-T. (2022). Convergent biological pathways underlying the Kallmann syndrome-linked genes Hs6st1 and Fgfr1. In Human Molecular Genetics (Vol. 31, Issue 24, pp. 4207–4216). Oxford University Press (OUP). https://doi.org/10.1093/hmg/ddac172
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Collection
Citation
Moon, S., & Zhao, Y.-T., Convergent biological pathways underlying the Kallmann syndrome-linked genes Hs6st1 and Fgfr1. Human Molecular Genetics, Volume 31, Issue 24, December 2022, pages 4207-4216, New York Tech Institutional Repository, accessed May 17, 2024, https://repository.nyitlibrary.org/items/show/3709
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