POI-associated EIF4ENIF1 mutations exhibit impaired translation regulation abilities

Yuxi Ding; Shuya Chen; Jing Jin; Yujun Sun; Chunfang Chu; Kehkooi Kee; Mingwei Xin; Lin Li

doi:10.1016/j.gene.2024.148456

POI-associated EIF4ENIF1 mutations exhibit impaired translation regulation abilities

Gene. 2024 Apr 9:917:148456. doi: 10.1016/j.gene.2024.148456. Online ahead of print.

Authors

Yuxi Ding¹, Shuya Chen², Jing Jin³, Yujun Sun², Chunfang Chu⁴, Kehkooi Kee¹, Mingwei Xin⁵, Lin Li⁶

Affiliations

¹ The State Key Laboratory for Complex, Severe, and Rare Diseases, SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
² Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital. Beijing 100006, China.
³ Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, China.
⁴ Department of Gynecology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital. Beijing 100026, China.
⁵ Department of Traditional Chinese Medicine, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing 100026, China. Electronic address: xinmingwei@ccmu.edu.cn.
⁶ Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital. Beijing 100006, China. Electronic address: linlithu@ccmu.edu.cn.

PMID: 38604507
DOI: 10.1016/j.gene.2024.148456

Abstract

Various genetic variants have been found to be associated with the clinical onset of premature ovarian insufficiency (POI). However, when measured in vitro, the functional influence of the variants can be difficult to determine. By whole-exome sequencing (WES) of 93 patients with sporadic POI, we found a missense variant c.623G > A;p.R208H in the EIF4ENIF1 gene. In silico prediction of the variant using different algorithms suggested it might be a damaging variant. We compared the property of EIF4ENIF1 R208H and Q842P, a POI-related mutant that we reported previously, with wildtype (WT) protein using 293FT cells in vitro. Surprisingly, a change in subcellular distribution and granule forming ability (Q842P) and nuclear import capacity (R208H) was not observed, despite domain prediction evidences. Since EIF4ENIF1 was reported to inhibit translation, we employed T&T-seq, a translation-transcription dual-omics sequencing method, to profile gene expression upon overexpression of EIF4ENIF1 WT and mutants. EIF4ENIF1 WT overexpression group exhibited significantly (P < 0.0001) lower translation efficiency (TE) than empty vector or GFP overexpression control group. Surprisingly, EIF4ENIF1 Q842P overexpression failed to repress global translation, showing an overall TE significantly higher than WT group. Overexpression R208H significantly (P < 0.0001) lowered the overall TE, whereas exhibiting a reduced translation inhibitory effect on high-TE genes (TE > 2 in GFP control group). Several fertility-associated genes, such as AMH in Q842P group and SERPINE1 and THBS1 in R208H group, was translationally up-regulated in mutant groups versus WT control, suggesting a potential mechanism of mutated EIF4ENIF1 causing POI via impaired translation repression. It is further proposed that T&T-seq can be a sensitive evaluation tool for the measurement of functional alteration by variants in many other translational regulator genes, not only EIF4ENIF1, helping to eliminate misinterpretation of clinical significance of genetic variants.

Keywords: EIF4ENIF1; Premature ovarian insufficiency; Transcriptome and translatome sequencing; Translation; Whole-exome sequencing.