Assessment of growth hormone gene polymorphism effects on reproductive traits in Holstein dairy cattle in Tunisia

Research to assess the effect of single genes on reproductive traits in bovine species is imperative to elucidate genes' functions and acquire a better perspective of quantitative traits. The present study was undertaken to characterize genetic diversity in the bovine growth hormone (GH) gene in a population of 410 Holstein dairy cows in Tunisia. The analyses were based on single nucleotide polymorphisms, and GH-AluI and GH-MspI detections and genotyping were carried out using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Data were analyzed using a mixed linear model with the MIXED procedure to reveal the possible effect of GH genotypes on reproductive traits. The frequency data of AluI(L//V) and MspI(+//−) alleles were 87.04//12.96 and 70.06//29.94, respectively. The distribution of the frequency of GH genotypes for LL/LV/VV and (−/−)//(+/−)//(+/+) were 77.75//18.59//3.66 and 15.37//29.13//55.50, respectively. The results of the statistical analyses proved that GH-AluI showed a substantial favorable effect on exanimate traits except for the age at first calving; however, only a suggestive effect of GH-MspI on the calving interval (CI) and the days open (DI) was found. The homozygous LL genotype seemed to be advantageous with respect to the CI and the DI compared with LV and VV genotypes. Heterozygous MspI(+/−) cows tended to have a longer CI and DI than MspI(+/+) and MspI(−/−) cows, but the difference was not statistically significant. A significant effect of different GH-AluI–MspI combined genotypes was found on the number of inseminations per conception, the CI and the DI, and the LL/– combined genotype seemed to be associated with better reproductive performance. Based on these results, the LL genotype of the GH locus can be considered to be a favorable genotype for reproductive traits in Holstein dairy cattle, although these findings need to be confirmed by further research before polymorphisms can be used in a marker-assisted selection program.</p

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways

Erratum: Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome (J. Exp. Med. (2020) 217:6 Doi:10.1084/jem.20191804)

The authors regret that in the original version of Table S1, the column for patient 12 was mistakenly duplicated in the column for patient 8. The online Table S1 PDF has been corrected. The error appears only in PDFs downloaded before June 4, 2020

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways

donor selection for adults and pediatrics

It is known that multiple factors impact on transplantation outcome; the heaviest ones are disease-related (disease refractoriness, phase, clonal abnormalities, etc. in malignancies and disease type and associated rejection risk in non-malignant diseases) and patient-related (age, comorbidities, infectious diseases/colonization, etc.). Moreover, donor-related issues and stem cell source may influence the extent of disease control and transplant-related mortality

Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity