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. 2020 Sep 22:11:557341.
doi: 10.3389/fgene.2020.557341. eCollection 2020.

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

Xinxian Deng  1 , He Fang  1 , Asha Pathak  2 , Angela M Zou  3 , Whitney Neufeld-Kaiser  1 , Emily A Malouf  4 , Richard A Failor  5 , Fuki M Hisama  4 , Yajuan J Liu  1
Affiliations

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

Xinxian Deng et al. Front Genet. .

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.

Keywords: CMC4; FUNDC2; Sertoli cell barrier; Xq28 deletion; apoptosis; hypergonadotropic hypogonadism.

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Figures

FIGURE 1
FIGURE 1
Family pedigree Circles indicate females, and squares indicate males. Diagonal lines designate deceased family members. Arrow indicates the proband. Remaining details are defined in the Key.
FIGURE 2
FIGURE 2
Characterization of Xq28 deletion. (A) 44.8 kb Xq28 deletion breakpoints (magenta lines) locate in a SINE element (breakpoint A) and intron 1 of CMC4 and MTCP1 (breakpoint B) as well as genes, H3K4me1/3 and H3K27Ac histone marks associated regulatory elements within and near the deletion on Xq28. (B) Relative expression levels of genes within and near the Xq28 deletion measured by RNA-seq. TPM, tags per million. (C) RT-PCR results for the expression of F8 and BRCC3 in peripheral blood. Error bars represent the standard deviation from the mean for three male or female controls.
FIGURE 3
FIGURE 3
Effect of Xq28 deletion on global gene expression in the patient. (A) Volcano diagram of differentially expressed genes (DEGs) in the patient versus control (Ctrl) males. Horizontal axis represents expression fold change changes (log2) and vertical axis represents FDR (log10). DEGs with | log2 fold change| > 1 and FDR < 0.01 were plotted. Down- or up-regulated DEGs are shown in blue or red, respectively. Overlapped DEGs that were significantly down- or up-regulated both in the patient versus control males and in the patient versus control females are also indicated by green or yellow, respectively. The number of these overlapped DEGs is present in the parenthesis. (B) Volcano diagram of DEGs in the patient versus control females. The same analysis is done as in (A).
FIGURE 4
FIGURE 4
Enriched biological process for up- or down-regulated genes in the patient. (A) Enriched biological process from Gene Ontology (GO) analysis for up- (red) or down-regulated (blue) in the patient versus control males. The top 20 enriched biological process are shown. FDR < 0.05 was used for the cutoff. Biological process with enrichment fold less than 1 were excluded. (B) Enriched biological process from GO analysis for down-regulated in the patient versus control females. The same analysis is done as in (A).
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