First Report Unveiling Genetic Etiopathogenesis of Anejaculation: Involvement of Alpha-1a Adrenergic Receptor Gene in a in Familial Cases

SS-02 [Erkek Üreme Sağlığı]

First Report Unveiling Genetic Etiopathogenesis of Anejaculation: Involvement of Alpha-1a Adrenergic Receptor Gene in a in Familial Cases

Shahrashoub Sharifi1, Murat Dursun2, Sukru Palanduz1, Ayla Sahin1, Ates Kadioglu2
1Department of Internal Medicine, Division of Medical Genetics, İstanbul University, İstanbul Faculty of Medicine, İstanbul, Turkey.
2Department of Urology, İstanbul University, İstanbul Faculty of Medicine, İstanbul, Turkey

AIM: Disorders affecting ejaculation is only one of the many factors which may contribute to the pathogenesis of infer- tility. The genetic etiopathogenesis underlying anejaculation is not clear. It is important to elucidate the genetic etiology of anejaculation with respect to treatment options and genetic counseling.

Material And Method: This study examines a 28-year-old male and his 62-year-old father, both experiencing infertility due to anejaculation, characterized by the inability to ejaculate semen during sexual activity. However, the father had two children conceived through microscopic testicular sperm extraction (micro-TESE) and intracytoplasmic sperm in- jection (ICSI) procedures. Conventional chromosome analysis and microdeletion of the Y chromosome analyses were performed for both individuals. Blood sugar (fasting), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and total testosterone levels were examined. Testes were assessed upon physical examination and ultra- sonographic imaging. The patients showed no signs of endocrine abnormalities, genital abnormalities, or neurological deficits that could contribute to ejaculatory dysfunction. The presence of a family history of similar symptoms or condi- tions served as a crucial criterion, indicating a potential genetic cause. Consequently, given that no gene associated with this disease has been identified, our initial approach involved investigating all coding regions. Therefore, Dual-based exome sequencing was performed using the MGISEQ-2000RS High-throughput Sequencing Set. Sanger sequencing was utilized to confirm the identified variant.

RESULT: We identified a novel variant in Alpha-1a Adrenergic Receptor (ADRA1A) in both patients. The identified variant (ENST00000380586.1:c.939G>T) affects a highly conserved aromatic region of the Alpha-1a Adrenergic Recep- tor (ADRA1A) which is the ligand (norepinephrine) binding site. It is also the same region where antagonistic drugs bind.

DISCUSSION: The Alpha-1a Adrenergic Receptor is known to play a significant role in regulating physiological func- tions in peripheral tissues, particularly in the prostate and urethra. We found that α1A-adrenoceptors, particularly the sub- type α1A, are crucial for normal contractility in the vas deferens and sperm ejaculation, as evidenced by studies in mice with targeted disruption of this receptor. Additionally, α1-adrenoceptor antagonists, commonly used to treat lower urinary tract symptoms, have been associated with ejaculatory dysfunction, indicating the involvement of α1A-adrenoceptors in ejaculation. Our patients had a missense mutation affecting a critical region of the Alpha-1a Adrenergic Receptor, which is involved in ligand binding. We proposed several mechanisms through which mutations in this receptor, beyond the ligand-binding site, could lead to anejaculation. These mechanisms include impaired receptor coupling with G-proteins, altered receptor trafficking, conformational changes in receptor structure, and dysregulated downstream signaling path- ways crucial for smooth muscle contraction. While our study sheds light on the potential genetic basis of anejaculation, further research is necessary to fully understand the functional consequences of these mutations and to develop targeted therapeutic interventions. Exploring these mechanisms will enhance our understanding of the pathophysiology of ane- jaculation and may lead to improved treatments for affected individuals. To our knowledge, this is the first report in the literature to date, and our findings may expand the knowledge on the field of anejaculation genetics.

Anahtar Kelimeler: Anejaculation, infertility, genetic etiology, ADRA1A