|LETTER TO THE EDITOR
|Ahead of print publication
Trio-based genome sequencing identifies candidate causal genes in lifelong premature ejaculation
Dao-Qi Wang1,2, Yang-Tian Jiao3, Le Ling1,2, Jia-Xin Wang1,2, Yong-Hua Niu4, Zhe Tang1,2, Yin-Wei Chen1,2, Jia-Nan Gong1,2, Tao Wang1,2, Ji-Hong Liu1,2, Qing Ling1,2
1 Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
2 Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
3 Department of Urology, China-Japan Friendship Hospital, Beijing 100029, China
4 Department of Pediatric Surgery Tongji Hospital, Tongji Medical College, Wuhan 430030, China
|Date of Submission||29-Nov-2019|
|Date of Acceptance||15-Jul-2020|
|Date of Web Publication||23-Oct-2020|
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030; Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030
Source of Support: None, Conflict of Interest: None
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|How to cite this URL:|
Wang DQ, Jiao YT, Ling L, Wang JX, Niu YH, Tang Z, Chen YW, Gong JN, Wang T, Liu JH, Ling Q. Trio-based genome sequencing identifies candidate causal genes in lifelong premature ejaculation. Asian J Androl [Epub ahead of print] [cited 2020 Nov 25]. Available from: https://www.ajandrology.com/preprintarticle.asp?id=298916
Premature ejaculation (PE) is the most common sexual dysfunction with prevalence rates of 20%–30%. Unfortunately, there are limited treatment options as a result of the lack of knowledge about the pathophysiology of PE. Although the exact etiology of PE is not clear, it is known that PE is etiologically heterogeneous, with both genetic and environmental factors playing a role. Schapiro and Waldinger's study suggested that PE ran in families, with a higher morbidity in the family members of PE patients than that in unaffected individuals., The results of Jern's study indicated that PE is moderately heritable, with an inheritability ratio of 28% in a cohort of 3946 pairs of twins.
Because the patients with lifelong PE suffer from symptoms beginning with the first sexual experience, we proposed that lifelong PE is driven more by genetic predisposition than by environmental factors. In this study, we recruited eight trios (healthy parents and a lifelong PE proband) to explore the genetic predisposition using whole-genome sequencing (WGS). It was also the first time that trio-based genome sequencing had been used to investigate the genetic basis of lifelong PE. In our study, we showed rare inherited novel mutations, de novo mutations, and autosomal recessive inherited mutations significantly contributed to lifelong PE.
In this study, all patients were diagnosed with lifelong PE in Tongji Hospital, Huazhong University of Science and Technology (Wuhan, China). Signed informed consent forms were provided by the probands and their parents. The Ethics Committee of Tongji Hospital approved our study (Approval No. 2017s321). The Chinese language version of the PE diagnostic tool (PEDT) was used to diagnose these patients. The diagnosis of lifelong PE was based on the clinical history of the probands. The intravaginal ejaculation latency time (IELT) of all probands was <1 min from the first sexual experience, indicating the presence of lifelong PE, and their PEDT scores were more than 15.
Through WGS, we identified 741 mutant genes, including 969 missense mutations in eight trios (proband and his unaffected parents). The summary of all mutations is shown in [Table 1]. There were 71 genes containing more than one mutation [Supplementary Figure 1 [Additional file 1]]a. Furthermore, we identified 60 mutant genes in more than one trio [Supplementary Figure 1]b. In eight trios, we identified 63 missense mutations in zinc finger protein 717 (ZNF717 ), a putative transcriptional regulator associated with many diseases, such as growth retardation, intellectual disability, and DiGeorge-like syndrome. Mutant carboxy-terminal domain small phosphatase 2 (CTDSP2 ) was found in all seven trios containing 23 missense mutations. CTDSP2 is the target gene of microRNA miR-26, and they work together to affect many biological processes, including differentiation of neurons, tumor cell growth, and cell cycle.
In our study, we identified 165 novel mutations in 158 genes [Table 1]. There were three novel missense mutations in CTDSP2 found in four trios, including p.Y262C, p.V261L, and p.P250S. We also found a mutant gene, FAT atypical cadherin 4 (FAT4 ), in trios H7 and H8. Badouelet al . reported that FAT4 affected mouse brain development by regulating neural tube closure and neural progenitor proliferation. Beste et al . also reported that FAT4 affected functional cerebral architecture. Lifelong PE patients cannot control ejaculation, which means that the central nervous system loses control of the ejaculation impulsion. The mutant FAT4 in our study might impair the central nervous system function of lifelong PE patients, resulting in the lack of control of ejaculation. The relationship between FAT4 and lifelong PE is worthy of further study to confirm this hypothesis.
Through trio-based genome sequencing, seven inherited autosomal recessive mutations were identified from five trios in our study. All the seven mutations were homozygous in probands and were heterozygous in their unaffected parents. In trio H2, two inherited autosomal recessive mutations, p.L52V in ZNF717 and p.D201G in cytochrome P450 family 4 subfamily F member 3(CYP4F3 ), were found. CYP4F3 encodes a member of the cytochrome P450 superfamily of enzymes. CYPs can metabolize both endogenous and exogenous substances, and one of the endogenous substrates of CYPs is neurotransmitters. We conjectured that this mutation in CYP4F3 might impair the enzyme function, leading to an imbalance in metabolism of neurotransmitters or other substances. The resultant imbalance in these substances might have a negative effect on the control of ejaculation impulsion.
In addition to the rare inherited mutations, we proposed that de novo germline mutations might contribute to the genetic architecture of lifelong PE. We found 12 de novo single-nucleotide variants (SNVs) in our study. There was an increased trend of the overall de novo mutation rate in the lifelong PE patients (1.5 events per proband on average) compared with that in controls (0.74 events per proband on average), with a lifelong PE/control rate ratio of 2.03. Overall, 5 of the 8 probands (62.5%) carried at least one de novo mutation, and 3 probands (37.5%) harbored more than two de novo mutations.
We performed Gene Ontology (GO) analyses of mutant genes including biological process (BP), cellular component (CC), and molecular function (MF), as shown in [Supplementary Figure 1]c, [Supplementary Figure 1]e, to find genes or signal pathways associated with lifelong PE. There were three BP-GO analysis items containing 6 genes, including positive regulation of secretion by cell (GO:1903532), regulation of mitotic cell cycle phase transition (GO:0090559), and positive regulation of secretion (GO:0051047). We could find six CC-GO analysis items with three genes involved, and nine MF-GO analysis items stood out. Our GO analyses results might provide the evidence of the relationship between secretion regulation and lifelong PE. In reported research, ejaculation could be regulated by the secretion and function of serotonin, dopamine, oxytocin, leptin, and vasopressin. It was suggested that the further study of the underlying causal mechanism of lifelong PE should focus on the regulation of secretion. Thus, we performed the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of mutant genes to explore which signal pathway might be involved in lifelong PE [Supplementary Figure 1]f. Unfortunately, the most relative item in our study was protein digestion and absorption (hsa04974), which seemed to have little relationship with lifelong PE.
In summary, we performed a trio-based study to genetically dissect lifelong PE using genome sequencing and identified candidate-associated genes or biological processes. However, we need a multicenter cohort study combined with functional experiments to better investigate the genetic factors of lifelong PE. Nevertheless, the discovery of these candidate genes provided insight into lifelong PE development and etiology, which expands our current understanding of lifelong PE. Furthermore, our data may contribute to the future study of causal mechanisms underlying lifelong PE and provide new targets for its treatment.
| Author Contributions|| |
QL and JHL designed the study. DQW, YTJ, LL, JXW, YHN, ZT, YWC, and JNG carried out the follow-up reviews and participated in clinical data collection. DQW and YTJ performed genome sequencing analysis. DQW drafted the article. QL and TW revised the article. All authors read and approved the final manuscript.
| Competing Interests|| |
All authors declared no competing interests.
| Acknowledgments|| |
The authors thank all the patients and their families for participating in this study. This study was funded by the National Natural Science Foundation of China (No. 81671443) and Tongji Hospital Clinical Research Flashship Program (No. 2019CR109).
Supplementary Information is linked to the online version of the paper on the Asian Journal of Andrology website.
| References|| |
Serefoglu EC, McMahon CG, Waldinger MD, Althof SE, Shindel A, et al
. An evidence-based unified definition of lifelong and acquired premature ejaculation: report of the second international society for sexual medicine ad hoc committee for the definition of premature ejaculation. Sex Med
2014; 2: 41–59.
Russo A, Capogrosso P, Ventimiglia E, La Croce G, Boeri L, et al
. Efficacy and safety of dapoxetine in treatment of premature ejaculation: an evidence-based review. Int J Clin Pract
2016; 9: 723–33.
Porst H, Montorsi F, Rosen RC, Gaynor L, Grupe S, et al
. The Premature Ejaculation Prevalence and Attitudes (PEPA) survey: prevalence, comorbidities, and professional help-seeking. Eur Urol
2007; 3: 816–23.
Waldinger MD, Rietschel M, Nöthen MM, Hengeveld MW, Olivier B. Familial occurrence of primary premature ejaculation. Psychiatr Genet
1998; 1: 37–40.
Schapiro B. Premature ejaculation: review of 1130 cases. J Urol
1943; 50: 374–9.
Jern P, Santtila P, Johansson A, Varjonen M, Witting K, et al
. Evidence for a genetic etiology to ejaculatory dysfunction. Int J Impot Res
2009; 1: 62–7.
Huang YP, Chen B, Ping P, Wang HX, Hu K, et al
. The premature ejaculation diagnostic tool (PEDT): linguistic validity of the Chinese version. J Sex Med
2014; 9: 2232–8.
Zhuang C, Wang P, Huang D, Xu L, Wang X, et al
. A double-negative feedback loop between EZH2 and miR-26a regulates tumor cell growth in hepatocellular carcinoma. Int J Oncol
2016; 3: 1195–204.
Badouel C, Zander MA, Liscio N, Bagherie-Lachidan M, Sopko R, et al
. Fat1 interacts with Fat4 to regulate neural tube closure, neural progenitor proliferation and apical constriction during mouse brain development. Development
2015; 16: 2781–91.
Beste C, Ocklenburg S, von der Hagen M, Di Donato N. Mammalian cadherins DCHS1-FAT4 affect functional cerebral architecture. Brain Struct Funct
2016; 5: 2487–91.