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Cell adhesion molecule L1 like plays a role in the pathogenesis of idiopathic hypogonadotropic hypogonadism

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A Correction to this article was published on 31 October 2022

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Abstract

Purpose

The pathogenesis of idiopathic hypogonadotropic hypogonadism (IHH) is genetically complex. The aims of this study were to investigate the genetic profile and clinical manifestation of IHH in a Chinese pedigree and to discover new IHH-associated genes.

Methods

The first step was to follow up the clinical phenotype and therapeutic outcomes of the pedigree in university hospital. The second step was that mutation screening was performed in this pedigree and 100 healthy controls. The third step was to further verify the pathogenicity of the discovered rare sequencing variant (RSV) by functional experiments. Whole exome sequencing, Sanger sequencing, testicular volume (TV), semen analysis, assessment of cell migration and necroptosis were performed.

Results

One heterozygous RSV (p.G517E) in CHL1 was identified in two male IHH patients and their mother in the pedigree, but not in healthy controls. All the three individuals exhibited olfactory impairment. hCG/hMG treatment significantly improved TV, serum testosterone and/or semen parameters of the two male patients. Functional analysis indicated that CHL1 significantly regulated GnRH neuronal cell line (GN11 cells) migration and necroptosis, with alteration of ERK1/2 activation, calcium loading, and transcription of RIPK3 and MLKL. However, the above processes were negatively influenced by the CHL1 RSV.

Conclusions

Our study reports the genetic relevance of CHL1 in IHH, and characterizes the phenotypic and therapeutic profiles in patients carrying the CHL1 RSV. CHL1 may act as a new IHH-associated gene, and should be taken into consideration in future investigations for this field.

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Acknowledgements

This study was supported by the grants from the National Natural Science Foundation of China (Project No. 81671443, 81601270). The authors would like to thank every individual of the pedigree for their trust, cooperation, and contribution in this research. Yinwei Chen especially would like to thank Zhao Wang, Christina Wang, and Xinyi Zeng.

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Author notes

  1. J. Liu and H. Xu contributed equally to the work.

Authors and Affiliations

  1. Institute of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Y. Chen, T. Sun, D. Wang, K. Liu, T. Wang, S. Wang, H. Xu & J. Liu

  2. Department of Urology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Y. Chen, T. Sun, D. Wang, K. Liu, T. Wang, S. Wang, H. Xu & J. Liu

  3. Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Y. Niu

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Ethical approval

This study was approved by the Ethical Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology and was conducted according to the principles of the Declaration of Helsinki.

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Informed consent was obtained from the subject, and this study considered Declaration of Helsinki as a statement of ethical principles.

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Supplementary Material 1 (DOCX 57 KB)

40618_2020_1485_MOESM2_ESM.jpg

Expression analysis of CHL1 in GN11 cells of differently transfected groups. (a) Representative Western blot results for CHL1-Flag (detected with antibody to Flag) of the three groups (the Control, CHL1-WT, CHL1-MUT groups) in GN11 cells. (b) The protein levels of CHL1-Flag with GAPDH as the loading control of the three groups. (c) Representative Western blot results for CHL1 of the four groups (the Control, CHL1-siRNA-1, CHL1-siRNA-2, CHL1-siRNA-3 groups) in GN11 cells. (d) The protein levels of CHL1 with GAPDH as the loading control of the four groups. *P < 0.05. RSV: rare sequencing variant; WT: wild type; MUT: mutant type (containing the CHL1 RSV); NS: no significant (JPG 490 KB)

40618_2020_1485_MOESM3_ESM.jpg

GO functional enrichment analysis of the differentially expressed genes. The enriched GO terms included biological process (a), cellular component (b) and molecular function (c). The length of bars indicates the number of DEGs. The color indicates P value. GO: Gene ontology; DEGs: differentially expressed genes (JPG 1184 KB)

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Chen, Y., Sun, T., Niu, Y. et al. Cell adhesion molecule L1 like plays a role in the pathogenesis of idiopathic hypogonadotropic hypogonadism. J Endocrinol Invest 44, 1739–1751 (2021). https://doi.org/10.1007/s40618-020-01485-1

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