The blood-testis barrier (BTB) is found between adjacent Sertoli cells in the testis where it creates a unique microenvironment for the development and maturation of meiotic and postmeiotic germ cells in seminiferous tubes. It is a compound proteinous structure, composed of several types of cell junctions including tight junctions (TJs), adhesion junctions and gap junctions (GJs). Some of the junctional proteins function as structural proteins of BTB and some have regulatory roles. The deletion or functional silencing of genes encoding these proteins may disrupt the BTB, which may cause immunological or other damages to meiotic and postmeiotic cells and ultimately lead to spermatogenic arrest and infertility. In this review, we will summarize the findings on the BTB structure and function from genetically-modified mouse models and discuss the future perspectives.

Purpose Fanconi anemia (FA) genes play important roles in spermatogenesis. In mice, disruption of Fancm impairs male fertility and testicular integrity, but whether FANCM pathogenic variants (PV) similarly affect fertility in men is unknown. Here we characterize a Pakistani family having three infertile brothers, two manifesting oligoasthenospermia and one exhibiting azoospermia, born to first-cousin parents. A homozygous PV in FANCM (c.1946_1958del, p.P648Lfs*16) was found cosegregating with male infertility. Our objective is to validate that FANCM p.P648Lfs*16 is the PV causing infertility in this family. Methods Exome and Sanger sequencing were used for PV screening. DNA interstrand crosslink (ICL) sensitivity was assessed in lymphocytes from patients. A mouse model carrying a PV nearly equivalent to that in the patients (Fancm^ΔC/ΔC) was generated, followed by functional analysis in spermatogenesis. Results The loss-of-function FANCM PV increased ICL sensitivity in lymphocytes of patients and Fancm^ΔC/ΔC spermatogonia. Adult Fancm^ΔC/ΔC mice showed spermatogenic failure, with germ cell loss in 50.2% of testicular tubules and round-spermatid maturation arrest in 43.5% of tubules. In addition, neither bone marrow failure nor cancer/tumor was detected in all the patients or adult Fancm^ΔC/ΔC mice. Conclusion These findings revealed male infertility to be a novel phenotype of human patients with a biallelic FANCM PV.

The Cell Division-Cycle-14 gene encodes a dual-specificity phosphatase necessary in yeast for exit from mitosis. Numerous disparate roles of vertebrate Cell Division-Cycle-14 (CDC14A) have been proposed largely based on studies of cultured cancer cells in vitro. The in vivo functions of vertebrate CDC14A are largely unknown. We generated and analyzed mutations of zebrafish and mouse CDC14A, developed a computational structural model of human CDC14A protein and report four novel truncating and three missense alleles of CDC14A in human families segregating progressive, moderate-to-profound deafness. In five of these families segregating pathogenic variants of CDC14A, deaf males are infertile, while deaf females are fertile. Several recessive mutations of mouse Cdc14a, including a CRISPR/Cas9-edited phosphatase-dead p.C278S substitution, result in substantial perinatal lethality, but survivors recapitulate the human phenotype of deafness and male infertility. CDC14A protein localizes to inner ear hair cell kinocilia, basal bodies and sound-transducing stereocilia. Auditory hair cells of postnatal Cdc14a mutants develop normally, but subsequently degenerate causing deafness. Kinocilia of germ-line mutants of mouse and zebrafish have normal lengths, which does not recapitulate the published cdc14aa knockdown morphant phenotype of short kinocilia. In mutant male mice, degeneration of seminiferous tubules and spermiation defects result in low sperm count, and abnormal sperm motility and morphology. These findings for the first time define a new monogenic syndrome of deafness and male infertility revealing an absolute requirement in vivo of vertebrate CDC14A phosphatase activity for hearing and male fertility.

The aim of this study was to determine the influence of vitamin D-binding protein (DBP) gene polymorphisms in vitamin D metabolites before and after vitamin D supplementation. In all, 234 participants (126 women; 108 men) with vitamin D deficiency [25(OH)D <50 nmol/L] were given 50 000 IU of vitamin D supplements for 8 wk followed by daily maintenance of 1000 IU for 4 mo. Two single-nucleotide polymorphisms (rs4588 and rs7041) in DBP coding gene were assessed. Baseline 25(OH)D was significantly in higher in participants with homozygous major genotype of rs7041 than other genotypes (P = 0.02). Postsupplementation 25(OH)D was significantly higher in participants with homozygous major genotypes of either rs4588 and rs7041 than other genotypes (P < 0.001). Participants with the minor allele of either rs4588 or rs7041 were 2.9 (1.9-4.5) times and 3.7 (2.1-6.6) times, respectively, more likely to be non-responders (postsupplementation 25 OHD <50 nmol/L) than those homozygous for the major allele at these locations (P < 0.001). Furthermore, participants with homozygous minor and heterozygous genotype of rs7041 were 6.2 and 4.2times more likely to be non-responders than those with the homozygous major genotype (P < 0.001) even after adjustments for age, sex, body mass index, baseline 25(OH)D concentration, and other alleles. Participants with homozygous minor and heterozygous genotypes of rs4588 were 4.1 and 12.4times more likely to be non-responders than those with homozygous major genotypes. These significant risks, however, were lost after adjustment. rs7041 and rs4588 variants of the DBP gene are associated with variations in 25(OH)D levels and efficacy of response to vitamin D supplementation in Saudi Arabian adults.

CDH2 (cadherin 2, Neural-cadherin, or N-cadherin) is the predominant protein of testicular basal ectoplasmic specializations (basal ES; a testis-spec