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Sex Chromosome Anomalies
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
L. Hamerton John, A. Evans Jane
SRY is a transcription factor whose function is to initiate testicular differentiation in mammalian embryogenesis. The protein contains a high mobility group box (HMG), a DNA binding motif conserved among a broad class of nuclear proteins. Almost all of the published mutations associated with sex reversal in 46,XY females are located in the HMG box and affect the structure of the DNA binding domain (146). Other loci involved in XY sex reversal include SOX9 at 17q24, a transcription factor whose duplication leads to XX sex reversal, while mutations lead to XY gonadal dysgenesis and campomelic dysplasia. Mutations in SF1 at 9q33 result in adrenal insufficiency and XY gonadal dysgenesis. Mutations in DMRT1 at 9p24 result in XY gonadal dysgenesis. Mutations at the DAX1 locus, an antitestis gene at Xp21.3, result in congenital adrenal hypoplasia, while duplications of a 160 kb region result in XY gonadal dysgenesis (158). Clearly, extensive genetic heterogeneity exists in both XX and XY sex reversal. The process of sex determination is clearly highly complex and only partially understood (153,158-160).
Computational characterization and integrative analysis of proteins involved in spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
Pranitha Jenardhanan, Manivel Panneerselvam, Premendu P. Mathur
In another study, Djureinovic et al. characterized the testis-specific proteome based on transcriptomics and antibody-based profiling and identified more than 1000 gene products that were testis-specific and further characterized them based on their location, such as in spermatogonia, spermatocytes, spermatids, sperm, Sertoli cells, and Leydig cells.43 The results reveal that doublesex- and mab-3-related transcription factor 1 (DMRT1) and P antigen family member 1 (PAGE1) are specific to spermatogonia. DMRT1 protein is involved in male sex determination and differentiation,44 while the function of PAGE1 is unknown. Similarly, the deleted-in-azoospermia-like (DAZL) gene product was reported to show high enrichment in spermatocytes, while the transition protein 1 (TNP1) gene and sperm mitochondria-associated cysteine-rich protein (SMCP) and actin-like protein 7B (ACTL7B) were specific to spermatid. Meanwhile, defensin, beta 119 (DEFB119) was found to be specific to Sertoli cell, the A kinase (PRKA) anchor protein 4 (AKAP4) was specific to Sertoli cell and glyceraldehyde-3-phosphate dehydrogenase (GAPDHS) gene products are specific to sperm. These findings provide useful insights into understanding the proteomic signature of testis.
Wnt signaling in spermatogenesis and male infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Vertika Singh, Meghali Joshi, Kiran Singh, Rajender Singh
Secreted Frizzled-related proteins (Sfrps) are secreted glycoproteins that are well-known antagonists of the canonical and noncanonical Wnt signaling pathways (29). Regulated expression of secreted Frizzled-related protein 1 (sFRP1) is required for spermatid adhesion and sperm release at spermiation (Figure 9.2). sFRP1 is known to regulate spermatid adhesion in testis by dephosphorylation of focal adhesion kinase and the nectin-3 adhesion protein complex (29). Interestingly, Sfrp1 and Sfrp2 null mouse embryos exhibit defects in reproductive tract maturation, gonadal positioning, morphology and external genitalia development (49). Doublesex and mab-3-related transcription factor 1, Dmrt1, is another factor that plays a crucial role in testis determination and differentiation. Dmrt1 has been shown to repress Wnt4 expression in chickens (50). Its high expression in testicular cells of fishes (44) and pigs (51) suggests that it determines the formation of the testis by inhibiting Wnt4. Recently, to investigate the role of dmrt1 in sex determination and gonad development, mutations disrupting this gene were studied in Zebrafish (52). They found that most of the dmrt1 mutant fishes developed as fertile females, suggesting a complete male-to-female sex reversal in mutant animals that would have otherwise developed as males. Few of the mutant animals developed as sterile males and displayed testicular dysgenesis, suggesting a crucial role of dmrt1 in male sex determination and testis development. Mutant dmrt1 males displayed aberrant gonadal development at the onset of gonad sex differentiation and reduced oocyte apoptosis followed by the development of intersex gonads and failed testis morphogenesis and spermatogenesis. By contrast, female ovaries developed normally (52). In addition, some positive effects of Wnt signaling on testis determination are also known. Wnt4 null gonads show a significant reduction in Sertoli cell numbers (53). Moreover, Wnt4 and Rspo1 null embryos display reduced Sertoli cell numbers, hypoplastic testis and few seminiferous tubules (53), suggesting a significant role of Wnt signaling in testicular development.
Update on the proteomics of male infertility: A systematic review
Published in Arab Journal of Urology, 2018
Manesh Kumar Panner Selvam, Ashok Agarwal
Fertility preservation has become an essential process in patients being treated for cancer. Generally, sperm concentration is low in ∼50% of patients with testicular cancer and 40% of patients with Hodgkin’s disease. Infertility is one of the noted side-effects of cancer treatment. Cancer treatment causes severe damage to the gonads and DNA of germ cells, thus affecting the fertilisation process. Cancers related to the reproductive system not only decrease the immunity of the system, but also have harmful effects on spermatogenesis [71]. Analysis of human testicular tissue using 2D-high-performance liquid chromatography–MS/MS detected that out of 7346 proteins, transmembrane protease, serine 12 (TMPRSS12); tubulin polymerisation promoting protein family member 2 (TPPP2); protease, serine 55 (PRSS55); doublesex and mab-3 related transcription factor 1 (DMRT1); piwi-like RNA-mediated gene silencing 1 (PIWIL1), and hemogen (HEMGN) were associated with cancer [72]. Our laboratory was the first to identify 398 DEPs [including the overexpression of PSA, prostatic acid phosphatase (PAcP), zinc α2-glycoprotein (ZAG), and SEMG1 and SEMG2, as well as under expression of A-kinase anchoring protein 4 (AKAP4) and dynein axonemal heavy chain 17 (DNAH17)] in patients with testicular cancer using a global proteomic approach. Mitochondrial dysfunction, oxidative phosphorylation, and tricarboxylic acid cycle were the major pathways dysregulated in the spermatozoa of patients with testicular cancer [73].
Contemporary genetics-based diagnostics of male infertility
Published in Expert Review of Molecular Diagnostics, 2019
Alberto Ferlin, Savina Dipresa, Andrea Delbarba, Filippo Maffezzoni, Teresa Porcelli, Carlo Cappelli, Carlo Foresta
Among them, deletions in 9p chromosome including the DMRT1 gene is particularly attractive as genetic cause of male infertility, even if with a very low frequency. DMRT1 is a testis-specific transcriptional regulator required for testicular differentiation mapping on chromosome 9p24.3, a region involved in XY gonadal dysgenesis [59]. Smaller deletions [60] and mutations [61] of this gene have been identified in patients with non-obstructive azoospermia without XY gonadal dysgenesis.
Molecular diagnostics of disorders of sexual development: an Indian survey and systems biology perspective
Published in Systems Biology in Reproductive Medicine, 2019
MR Nagaraja, Satya Prakash Gubbala, C. R. Wilma Delphine Silvia, Ramars Amanchy
DMRT1 is one gene for which we could not find high confidence associations using our approach. However, it is gonad-specific and has sexually dimorphic expression profile. It plays a major role in sex determination, and interestingly it was observed that high DMRT1 expression works toward testicular differentiation, and lower expression is attuned toward ovarian differentiation (Smith et al. 1999).