Deletion of FUNDC2 and CMC4 on Chromosome Xq28 Is Sufficient to Cause Hypergonadotropic Hypogonadism in Men

Abstract

Background: Hypergonadotropic hypogonadism (HH) is characterized by low sex steroid levels and secondarily elevated gonadotropin levels with either congenital or acquired etiology. Genetic factors leading to HH have yet to be fully elucidated. Methods: Here, we report on genome and transcriptome data analyses from a male patient with HH and history of growth delay who has an inherited deletion of chromosome Xq28. Expression analyses were done for this patient and his unaffected family members and compared to normal controls to identify dysregulated genes due to this deletion. Results: Our patient's Xq28 deletion is 44,806 bp and contains only two genes, FUNDC2 and CMC4. Expression of both FUNDC2 and CMC4 are completely abolished in the patient. Gene ontology analyses of differentially expressed genes (DEGs) in the patient in comparison to controls show that significantly up-regulated genes in the patient are enriched in Sertoli cell barrier (SCB) regulation, apoptosis, inflammatory response, and gonadotropin-releasing regulation. Indeed, our patient has an elevated follicle stimulating hormone (FSH) level, which regulates Sertoli cell proliferation and spermatogenesis. In his mother and sister, who are heterozygous for this deletion, X-chromosome inactivation (XCI) is skewed toward the deleted X, suggesting a mechanism to avoid FSH dysregulation. Conclusion: Compared to the previously reported men with variable sized Xq28 deletions, our study suggests that loss of function of FUNDC2 and CMC4 results in dysregulation of apoptosis, inflammation, and FSH, and is sufficient to cause Xq28-associated HH.

The Genetic Etiology Diagnosis of Fetal Growth Restriction Using Single-Nucleotide Polymorphism-Based Chromosomal Microarray Analysis

“…As shown in the database, there are cases with similar and smaller deletions than the fragment exhibiting developmental delay and ventricular septal defect. Moreover, a previous study showed that a patient who harbored a deletion of chromosome Xq28 exhibited growth delay (19). Ultrasound in this case showed ventricular septal defect and FGR, which was similar to the clinical phenotypes reported in the database and literature.…”

Single‐cell RNA sequencing of the Mongolia sheep testis reveals a conserved and divergent transcriptome landscape of mammalian spermatogenesis

“…53 FUNDC2 has been reported to be involved in apoptosis, inflammation, and FSH dysregulation, which is important for regulating Sertoli cell proliferation and spermatogenesis. 54 Current studies have not found that TSPAN6 is closely related to spermatogenesis, but studies have shown that TSPAN6 is a negative regulator of RLR pathway mediated immune signal transduction. 55 Collectively, the function of these genes in spermatogenesis remains to be studied, but they can be used as germ cell marker genes in different stages of spermatogenesis.…”

“…AKAP4 regulates signal transduction and metabolic pathways that support sperm motility and capacitation and is highly expressed in RStd 53 . FUNDC2 has been reported to be involved in apoptosis, inflammation, and FSH dysregulation, which is important for regulating Sertoli cell proliferation and spermatogenesis 54 . Current studies have not found that TSPAN6 is closely related to spermatogenesis, but studies have shown that TSPAN6 is a negative regulator of RLR pathway mediated immune signal transduction 55 .…”