Defective Leukocyte Adhesion and Chemotaxis Contributes to Combined Immunodeficiency in Humans with Autosomal Recessive MST1 Deficiency.

PURPOSE: To investigate the clinical and functional aspects of MST1 (STK4) deficiency in a profoundly CD4-lymphopenic kindred with a novel homozygous nonsense mutation in STK4. Although recent studies have described the cellular effects of murine Mst1 deficiency, the phenotype of MST1-deficient human lymphocytes has yet to be fully explored. Patient lymphocytes were therefore investigated in the context of current knowledge of murine Mst1 deficiency. METHODS: Genetic etiology was identified by whole exome sequencing of genomic DNA from two siblings, combined with linkage analysis in the wider family. MST1 protein expression was assessed by immunoblotting. The ability of patient lymphocytes to adhere to ICAM-1 under flow conditions was measured, and transwell assays were used to assess chemotaxis. Chemokine receptor expression was examined by flow cytometry and receptor signalling by immunoblotting. RESULTS: A homozygous nonsense mutation in STK4 (c.442C > T, p.Arg148Stop) was found in the patients, leading to a lack of MST1 protein expression. Patient leukocytes exhibited deficient chemotaxis after stimulation with CXCL11, despite preserved expression of CXCR3. Patient lymphocytes were also unable to bind effectively to immobilised ICAM-1 under flow conditions, in keeping with a failure to develop high affinity binding. CONCLUSION: The observed abnormalities of adhesion and migration imply a profound trafficking defect among human MST1-deficient lymphocytes. By analogy with murine Mst1 deficiency and other defects of leucocyte trafficking, this is likely to contribute to immunodeficiency by impairing key aspects of T-cell development and function such as positive selection in the thymus, thymic egress and immune synapse formation in the periphery.This is thepublished version. It first appeared at http://link.springer.com/article/10.1007%2Fs10875-016-0232-2

Interactions and regulation of the cycle proteins Esco2 and MLF1IP

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Nutrigenomics: the role of nutrients in gene expression

Improved understanding of the mechanism behind periodontal tissue destruction, the potential protective role of nutrients and the advent of modern genomic measurement tools has led to an increased interest in the association between nutrition and periodontal disease. To date, evidence for a direct link between periodontal disease and nutrition has come mainly from large observational cross‐sectional studies or very small double‐blind randomized supplementation trials, with a large proportion finding no significant association between the nutrient being analyzed and markers of periodontal disease status. The advent of the ‘genomic era’ has introduced the concept of nutrigenomic studies, which aim to reveal the relationship between nutrition and the genome to provide a scientific basis for improved public health through dietary means. Used alongside relatively inexpensive high‐throughput technology, this will allow the effect of diet on the etiology of periodontal disease to be studied in greater detail. As it is extremely likely that interactions between genotype and diet are important in determining the risk of the most common complex diseases, it is highly probable that these interactions will be important in determining periodontal disease risk. Numerous nutritional genetic studies where the outcome measures have been markers of disease risk, most notably cardiovascular disease and cancer, provide proof of principle, highlight the importance of understanding these interactions and illustrate where the effect of dietary modification on periodontal disease progression may have been overlooked previously by observational studies

An essential role for the Zn2+ transporter ZIP7 in B cell development

Despite the known importance of zinc for human immunity, molecular insights into its roles have remained limited. Here we report a novel autosomal recessive disease characterized by absent B cells, agammaglobulinemia and early onset infections in five unrelated families. The immunodeficiency results from hypomorphic mutations of SLC39A7, which encodes the endoplasmic reticulum-to-cytoplasm zinc transporter ZIP7. Using CRISPR-Cas9 mutagenesis we have precisely modeled ZIP7 deficiency in mice. Homozygosity for a null allele caused embryonic death, but hypomorphic alleles reproduced the block in B cell development seen in patients. B cells from mutant mice exhibited a diminished concentration of cytoplasmic free zinc, increased phosphatase activity and decreased phosphorylation of signaling molecules downstream of the pre-B cell and B cell receptors. Our findings highlight a specific role for cytosolic Zn2+ in modulating B cell receptor signal strength and positive selection