Search

The current study aimed to investigate determinants of severity in a previously healthy patient who experienced two life-threatening infections, from West Nile Virus and SARS-CoV2. During COVID19 hospitalization he was diagnosed with a thymoma, retrospectively identified as already present at the time of WNV infection. Heterozygosity for p.Pro554Ser in the TLR3 gene, which increases susceptibility to severe COVID-19, and homozygosity for CCR5 c.554_585del, associated to severe WNV infection, were found. Neutralizing anti-IFN-α and anti-IFN-ω auto-antibodies were detected, likely induced by the underlying thymoma and increasing susceptibility to both severe COVID-19 pneumonia and West Nile encephalitis., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Context: Maturity-onset diabetes of the young (MODY) 8 is a rare form of monogenic diabetes characterized by a mutation in CEL (carboxyl ester lipase) gene, which leads to exocrine pancreas dysfunction, followed by β cell failure. Induced pluripotent stem cells can differentiate into functional β cells. Thus, β cells from MODY8 patients can be generated in vitro and used for disease modelling and cell replacement therapy., Methods: A genetic study was performed in a patient suspected of monogenic diabetes., Results: A novel heterozygous pathogenic variant in CEL (c.1818delC) was identified in the proband, allowing diagnosis of MODY8. Three MODY8-iPSC (induced pluripotent stem cell) clones were reprogrammed from skin fibroblasts of the patient, and their pluripotency and genomic stability confirmed. All 3 MODY8-iPSC differentiated into β cells following developmental stages. MODY8-iPSC-derived β cells were able to secrete insulin upon glucose dynamic perifusion. The CEL gene was not expressed in iPSCs nor during any steps of endocrine differentiation., Conclusion: iPSC lines from a MODY8 patient with a novel pathogenic variant in the CEL gene were generated; they are capable of differentiation into endocrine cells, and β cell function is preserved in mutated cells. These results set the basis for in vitro modelling of the disease and potentially for autologous β cell replacement., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Study Question: Can whole exome sequencing (WES) reveal a novel pathogenic variant in asthenozoospermia in a multiplex family including multiple patients?, Summary Answer: Patients were discovered to be homozygous for a rare 2-bp deletion in the ADCY10 coding region (c.1205_1206del, rs779944215)., What Is Known Already: ADCY10 encodes for soluble adenylyl cyclase (sAC), which is the predominant adenylate cyclase in sperm. It is already established that proper sAC activity and a constant supply of cAMP are crucial to sperm motility regulation, and knockout mouse models have been reported as severely asthenozoospermic. ADCY10 is a susceptibility gene for dominant absorptive hypercalciuria (OMIM#143870); however, no ADCY10 variations have been confirmed to cause human asthenozoospermia to date., Study Design, Size, Duration: This was a retrospective genetics study of a highly consanguineous pedigree of asthenozoospermia. The subject family was recruited in Iran in 2016., Participants/materials, Setting, Methods: The two patients were diagnosed as asthenozoospermic through careful clinical investigations. Both patients, respective parents, and an unaffected brother were subjected to WES. The discovered variant was validated by Sanger sequencing and segregated with the phenotype. To confirm the pathogenicity of the variant, sperm samples from both patients, 10 normozoospermic men and 10 asthenozoospermic patients not representing the variation, were treated with a cAMP analogue dissolved in human tubal fluid medium, followed by computer-assisted sperm analysis and statistical analyses., Main Results and the Role of Chance: The discovered homozygous variant occurs at 10 amino acids upstream of the ADCY10 nucleotide binding site leading to a premature termination (p.His402Argfs*41). Treatment of the patients' sperm samples with a cell-permeable cAMP analogue resulted in a significant increase in sperm motility, indicating the pathogenic role of the variant. Moreover, absorptive hypercalciuria, segregating within the family, was also associated with the same variant following a dominant inheritance., Limitations, Reasons for Caution: Though nonsense-mediated decay is highly likely to occur in the mutated transcripts, we were not able to confirm this due to low RNA levels in mature sperm., Wider Implications of the Findings: Our finding enlarges the phenotypic spectrum associated with the ADCY10 gene, previously described as a susceptibility gene for dominant absorptive hypercalciuria., Study Funding/competing Interest(s): This study was supported by grants from the Royan Institute, Tehran, Iran, and San Raffaele Hospital, Milan, Italy. The authors have no conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)