A functional spectrum of PROKR2 mutations identified in isolated hypogonadotropic hypogonadism.

Xinying Wang, Danna Chen, Yaguang Zhao, Meichao Men, Zhiheng Chen, Fang Jiang, Ruizhi Zheng, Maria I Stamou, Lacey Plummer, Ravikumar Balasubramanian, Jia-Da Li

Human molecular genetics 2023 May 05

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Isolated hypogonadotropic hypogonadism (IHH) is a rare disease with hypogonadism and infertility caused by the defects in embryonic migration of hypothalamic gonadotropin-releasing hormone (GnRH) neurons, hypothalamic GnRH secretion or GnRH signal transduction. PROKR2 gene, encoding a G-protein coupled receptor PROKR2, is one of the most frequently mutated genes identified in IHH patients. However, the functional consequences of several PROKR2 mutants remain elusive. In this study, we systematically analyzed the Gαq, Gαs and ERK1/2 signaling of 23 IHH-associated PROKR2 mutations which are yet to be functionally characterized. We demonstrate that blockage of Gαq, instead of MAPK/ERK pathway, inhibited PROK2-induced migration of PROKR2-expressing cells, implying that PROKR2-related IHH results primarily due to Gαq signaling pathway disruption. Combined with previous reports, we categorized a total of 63 IHH-associated PROKR2 mutations into four distinct groups according Gαq pathway functionality: (i) neutral (N, >80% activity); (ii) low pathogenicity (L, 50-80% activity); (iii) medium pathogenicity (M, 20-50% activity) and (iv) high pathogenicity (H, <20% activity). We further compared the cell-based functional results with in silico mutational prediction programs. Our results indicated that while Sorting Intolerant from Tolerant predictions were accurate for transmembrane region mutations, mutations localized in the intracellular and extracellular domains were accurately predicted by the Combined Annotation Dependent Depletion prediction tool. Our results thus provide a functional database that can be used to guide diagnosis and appropriate genetic counseling in IHH patients with PROKR2 mutations. © The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Citation

Xinying Wang, Danna Chen, Yaguang Zhao, Meichao Men, Zhiheng Chen, Fang Jiang, Ruizhi Zheng, Maria I Stamou, Lacey Plummer, Ravikumar Balasubramanian, Jia-Da Li. A functional spectrum of PROKR2 mutations identified in isolated hypogonadotropic hypogonadism. Human molecular genetics. 2023 May 05;32(10):1722-1729