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Approximately 10%–15% of couples worldwide are infertile, and male factors account for approximately half of these cases. Teratozoospermia is a major cause of male infertility. Although various mutations have been identified in teratozoospermia, these can vary among ethnic groups. In this study, we performed whole‐exome sequencing to identify genetic changes potentially causative of teratozoospermia. Out of seven genes identified, one, ATP/GTP Binding Protein 1 (AGTPBP1), was characterized, and three missense changes were identified in two patients (Affected A: p.Glu423Asp and p.Pro631Leu; Affected B: p.Arg811His). In those two cases, severe sperm head and tail defects were observed. Moreover, AGTPBP1 localization showed a fragmented pattern compared to control participants, with specific localization in the neck and annulus regions. Using murine models, we found that AGTPBP1 is localized in the manchette structure, which is essential for sperm structure formation. Additionally, in Agtpbp1‐null mice, we observed sperm head and tail defects similar to those in sperm from AGTPBP1‐mutated cases, along with abnormal polyglutamylation tubulin and decreasing △−2 tubulin levels. In this study, we established a link between genetic changes in AGTPBP1 and human teratozoospermia for the first time and identified the role of AGTPBP1 in deglutamination, which is crucial for sperm formation. [ABSTRACT FROM AUTHOR]

Objective: Fcγ receptor IIb (FcγRIIb) is an essential negative regulator of B cells that blocks B cell receptor (BCR) signaling and triggers c‐Abl–dependent apoptosis of B cells. FcγRIIb‐deficient mice display splenomegaly with expansion of B cells, leading to lupus. FcγRIIb‐I232T is a hypofunctional polymorphism associated with lupus susceptibility in humans, an autoimmune disease linked to diminished deletion of autoreactive B cells. In the context of the FcγRIIb‐I232T polymorphism, we investigated the role of FcγRIIb in the deletion of low‐affinity germinal center (GC) B cells, an important mechanism for preventing autoimmunity. Methods: We generated FcγRIIb232T/T mice to mimic human FcγRIIb‐I232T carriers and immunized mice with chicken gamma globulin (CGG)–conjugated NP, a T cell–dependent antigen, to examine the response of GC B cells. Results: Compared to wild‐type (WT) mice, FcγRIIb232T/T mice showed increased numbers of low‐affinity NP‐specific IgG and NP‐specific B cells and plasma cells; additionally, the expression of a somatic mutation (W33L) in their VH186.2 genes encoding high‐affinity BCR was reduced. Notably, FcγRIIb232T/T mice had a higher number of GC light zone B cells and showed less apoptosis than WT mice, despite having equivalent follicular helper T cell numbers and function. Moreover, phosphorylation of c‐Abl was reduced in FcγRIIb232T/T mice, and treatment of WT mice with the c‐Abl inhibitor nilotinib during the peak of GC response resulted in reduced affinity maturation reminiscent of FcγRIIb232T/T mice. Conclusion: Our findings provide evidence of a critical role of FcγRIIb/c‐Abl in the negative selection of GC B cells in FcγRIIb232T/T mice. Importantly, our findings indicate potential benefits of up‐regulating FcγRIIb expression in B cells for treatment of systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

Cadherin‐17 is an adhesion molecule expressed specifically in intestinal epithelial cells. It is frequently underexpressed in human colorectal cancer. The physiological function of cadherin‐17 and its role in tumourigenesis have not yet been determined. We used the transcription activator‐like effector nuclease technique to generate a Cdh17 knockout (KO) mouse model. Intestinal tissues were analysed with histological, immunohistochemical and ultrastructural methods. Colitis was induced by oral administration of dextran sulphate sodium (DSS), and, to study effects on intestinal tumourigenesis, mice were given azoxymethane (AOM) and DSS to induce colitis‐associated cancer. Cdh17 KO mice were viable and fertile. The histology of their small and large intestines was similar to that of wild‐type mice. The junctional architecture of the intestinal epithelium was preserved. The loss of cadherin‐17 resulted in increased permeability and susceptibility to DSS‐induced colitis. The AOM/DSS model demonstrated that Cdh17 KO enhanced tumour formation and progression in the intestine. Increased nuclear translocation of Yap1, but not of β‐catenin, was identified in the tumours of Cdh17 KO mice. In conclusion, cadherin‐17 plays a crucial role in intestinal homeostasis by limiting the permeability of the intestinal epithelium. Cadherin‐17 is also a tumour suppressor for intestinal epithelia. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The deadenylase nocturnin (Noc, Ccrn4l) has been recently found to regulate lipid metabolism and to control preadipocyte differentiation. Here, we showed that among the five deadenylases tested, Noc and Pan2 exhibited a biphasic expression which is out of phase to each other during adipocyte differentiation of 3T3-L1 cells. The expression levels of other deadenylases, including Parn, Ccr4, and Caf1, were relatively unchanged or reduced. The immediate early expressed Noc during 3T3-L1 adipogenesis was involved in regulating mitotic clonal expansion (MCE) and cyclin D1 expression, as demonstrated in Noc-silenced 3T3-L1 cells and Noc−/− primary mouse embryonic fibroblasts (MEFs). Transcriptional profiling of Noc-depleted 3T3-L1 adipocytes revealed that most of the differentially expressed genes were related to cell growth and proliferation. In human adipose tissue, NOC mRNA level negatively associated with both fasting serum insulin and homeostasis model assessment of insulin resistance, and positively associated with both adiponectin mRNA levels and circulating adiponectin levels. Taken together, these results suggest the role of Noc in the modulation of early adipogenesis as well as systemic insulin sensitivity. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: To explore the genetic characteristics of branchio-oto-renal (BOR) syndrome in an East Asian population. Study Design: Prospective clinical genetic study. Methods: Twelve families (total of 18 patients) who fulfilled the criteria for BOR syndrome were enrolled in this study. Mutation screening of the EYA1, SIX1, and SIX5 genes was performed by direct sequencing and quantitative polymerase chain reaction, and genotype-phenotype correlation was investigated. Results: Two novel EYA1 variants, c.466C>T (p.Q156X) and c.1735delG (p.D579fs), were identified in two multiplex families. The c.466C>T variant resulted in a truncated EYA1 protein, whereas the c.1735delG variant was predicted to encode an EYA1 protein with an abnormal C terminal. Neither variant was identified in a panel of 100 normal controls, and both were cosegregated with the BOR phenotype in the pedigrees, indicating that they were pathogenic mutations. No SIX1 and SIX5 mutations were detected in members of the remaining 10 families. Analysis of the genotype-phenotype correlation revealed a high phenotypic variability between and within BOR families. Conclusions: Two novel EYA1 mutations (c.466C>T and c.1735delG) were identified in two families with BOR syndrome. SIX1 and SIX5 mutations were not detected in the present study. Further investigation is warranted regarding the contribution of SIX1 and SIX5 mutations to BOR syndrome in East Asian populations. [ABSTRACT FROM AUTHOR]

Mutations in the gene encoding PIG-A (phosphatidylinositol glycan class A) are found in patients with paroxysmal nocturnal haemoglobinuria (PNH), an acquired haematopoietic stem cell disorder. Individuals with hereditary PIG-A mutations have never been identified, which is also manifested by the difficulties in generating Pig-a knockout (KO) mice. This study investigated the effect of Pig-a mutations on the development of visceral and genital organs in addition to the haematopoietic system by the generation of Pig-a KO chimaeric mice. Of a total of 54 live births out of 1684 blastocysts injected, chimaerism for Pig-a knockout was detected in 29 mice, suggesting the importance of Pig-a in embryogenesis and in live birth. Quantification of the degree of chimaerism in different organs of the surviving chimaeric mice revealed extremely low levels of Pig-a KO cells in the liver and spleen. In contrast, high levels of KO signals were usually detected in the brain, heart, lung and kidney. Haematopoiesis proceeded normally in these chimaeric mice (as measured by ‘complete blood cell counting’) and the Pig-a KO cells were present at low levels in red blood cells and B lymphocytes but at high levels in T lymphocytes, although these KO cells did not gain any growth advantage. The effect of Pig-a knockout was also prominent in the reproductive system, another organ with high mitotic activity. Breeding the male chimaeras revealed a high rate of infertility and abnormality in the male genital organs, including abnormally shaped testes, epididymis and seminal vesicles. Even in the absence of gross abnormalities of the genital organs, low counts of motile sperm were also discernible. Pig-a KO sperm was detected in these organs; however, no transmission of the KO allele was observed. The results suggest a possible mechanism underlying the non-transmission of the Pig-a KO gene in germlines. [ABSTRACT FROM AUTHOR]