Establishing the role of ZBTB20 mutations in GnRH deficiency and impaired neurogenesis in the subventricular zone: a human cohort and animal model study.

Overview

1. Furong Laboratory, Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, PR China
2. Hunan Key Laboratory of Animal Models for Human Diseases, Changsha, Hunan 410078, PR China
3. Hunan Key Laboratory of Medical Genetics, Changsha, Hunan 410078, PR China
4. Medical Genetic Center, Jiangxi Maternal and Child Health Hospital, No 318, Bayi Avenue, Nanchang, China
5. Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
6. NHC Key Laboratory of Endocrinology, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
7. Department of Laboratory Animals, Central South University, Changsha, Hunan 410078, China
8. MOE Key Laboratory of Rare Pediatric Diseases, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, PR China
9. Department of Basic Medical Sciences, Changsha Medical University, Changsha, Hunan 410219, China
10. Department of Endocrinology, The People’s Hospital of Henan Province, Zhengzhou, Henan 450003, China
11. Department of Clinical Nutrition, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China
12. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410078, China

Abstract

Background: Congenital hypogonadotropic hypogonadism (CHH) arises from defective development or dysfunction of GnRH neurons. Olfactory bulb (OB) malformations frequently accompany CHH, a condition termed Kallmann syndrome (KS). Nevertheless, approximately 50% of CHH cases remain genetically undefined.

Methods: Leveraging our 15-year effort in building one of Asia’s largest CHH cohorts (812 unrelated patients, and 49 CHH families), we identified a pathogenic ZBTB20 mutation (p.R300C) in a four-generation CHH family with seven affected members. We generated nervous system-specific Zbtb20 conditional knockout (cKO) mice to assess phenotypic and mechanistic consequences. Molecular analyses, including transcriptional regulation assays, were performed to explore downstream pathways.

Findings: Four additional heterozygous ZBTB20 variants were detected in the CHH cohort. Zbtb20 cKO mice recapitulated hallmark CHH features: GnRH neuron deficiency, hypogonadism, and infertility. Notably, migration of GnRH neurons in Zbtb20-deficient embryos was stalled along the defective terminal nerve (TN) scaffold. Furthermore, Zbtb20 deficiency impaired proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) and disrupted their migration via the rostral migratory stream (RMS) to the OB. We also identified Thbs4 as a key downstream target, as ZBTB20 transcriptionally activates Thbs4, which is critical for SVZ NSCs migration.

Interpretation: Our study establishes ZBTB20 as a CHH-associated gene and demonstrates its essential role in SVZ-OB neurogenesis. Loss of ZBTB20 function leads to OB atrophy, disrupted terminal nerves, GnRH deficiency and CHH pathogenesis.

Funding: This project is financially supported by National Natural Science Foundation of China, and the Natural Science Foundation of Hunan Province.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE308208, at NCBI GEO; found in “Data sharing statement”

Data sharing statement

The RNA-seq and WES data generated in this study have been deposited in public repositories under accession numbers (GSE308208 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE308208)). Human genetic data are available under managed access to protect participant privacy. Requests can be directed to corresponding author () and will be processed within four weeks. All other data supporting the findings are available within the article and its Supplementary materials.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 11 authors, 4 keywords, 18 MeSH terms, 3 funders, 51 references, 10 RRIDs.

Cite

This paper

Guan, J., Zhu, J., Li, Y., Nie, M., Zhang, J., Chen, Z., Liu, H., Chen, D.-N., Zheng, R., Men, M., & Li, J.-D. (2026). Establishing the role of ZBTB20 mutations in GnRH deficiency and impaired neurogenesis in the subventricular zone: a human cohort and animal model study. EBioMedicine, 131, 106416. https://doi.org/10.1016/j.ebiom.2026.106416

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