Clinical and Functional Analysis of a HABP4 Missense Variant in Chinese Han Women With Endometriosis

Background: Endometriosis (EM) is a complex gynecological disease whose underlying molecular mechanisms remain poorly understood. The discovery of cancer driver mutations in endometriotic lesions indicates that EM may share common molecular pathways with malignant tumors. Our previous whole-exome sequencing (WES) results revealed a rare heterozygous missense variant in the coding region of the Hyaluronan-binding protein 4 (HABP4) gene (rs200039443, c.1135C>T, p.R379W), which exhibited a significant difference in frequency between ovarian EM patients and control women. This study aimed to validate the HABP4 rare variant (p.R379W) in EM patients and explored its potential role in the pathogenic process of EM.Methods: Sanger sequencing was performed to validate the HABP4 rare variant (p.R379W) in EM patients, and intergroup comparison was conducted to explore the relationship between HABP4 variant and clinical characteristics. Additionally, in silico analysis was used to predict the pathogenicity of this variant. Construct plasmids of wild-type and mutant HABP4, transfect to ThESCs/Ishikawa cells, and detect cell migration, invasion and proliferation with Transwell and cell counting Kit-8 (CCK-8) assay.Results: The HABP4 rare variant (p.R379W) was identified in 7 of 300 patients with ovarian EM (2.33%), compared with 5 of 779 control women (0.64%) (p = 0.0452). Intergroup comparison demonstrated that levels of total bile acid (TBA), triglyceride (TG), uric acid (UA) and luteinizing hormone (LH) were significantly lower in the HABP4 variant group than in the wild-type group. Functional experiments showed that this variant promoted cell migration and invasion but exerted no effect on cell proliferation.Conclusion: These findings indicate that the HABP4 heterozygous variant (p.R379W) may be associated with the pathogenesis of EM and can be considered as “novel molecular insights” for this disease pathogenesis. Moreover, the present study enriches the spectrum of EM-associated gene mutations in the Chinese population.