Understanding the immunological impact of the human mutation explosion

Andrews, T. Daniel; Sjollema, Geoffrey; Goodnow, Christopher C.

doi:10.1016/j.it.2012.12.001

Cited by 13 publications

(20 citation statements)

References 71 publications

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“…On the contrary, Polyphen2 is a structure-based and sequence-based method that predicts the impact of amino acid allelic variants. They are both widely used to predict the function of mutations (Andrews et al, 2013). However, along with their increasingly popular use in recent years, numerous mutation alleles have been predicted to be a possible pathogenic cause of diseases, and whether these deleterious variants have an impact on the corresponding protein or not still remains largely unknown (Miosge et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Targeted Next-Generation Sequencing Successfully Detects Causative Genes in Chinese Patients with Hereditary Hearing Loss

Chen

Dong

Wang

et al. 2016

Genetic Testing and Molecular Biomarkers

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Section: Discussionmentioning

confidence: 99%

Targeted Next-Generation Sequencing Successfully Detects Causative Genes in Chinese Patients with Hereditary Hearing Loss

Chen

Dong

Wang

et al. 2016

Genetic Testing and Molecular Biomarkers

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“…An even greater challenge will be to predict the effects of combinations of variants, such as compound heterozygous missense mutations at a single locus, or composite heterozygosity or homozygosity for several loci in a common pathway (51). Allelic variation in TCR signal transduction is a key illustration of this challenge, where hypomorphic variants at different points in the pathway can have paradoxical outcomes (20).…”

Section: Discussionmentioning

confidence: 99%

Quantitative Reduction of the TCR Adapter Protein SLP-76 Unbalances Immunity and Immune Regulation

Siggs

Miosge

Daley

et al. 2015

The Journal of Immunology

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Gene variants that disrupt T cell receptor signaling can cause severe immune deficiency, yet less disruptive variants are sometimes associated with immune pathology. Null mutations of the gene encoding the scaffold protein SLP-76, for example, cause an arrest of T cell positive selection, while a synthetic membrane-targeted allele allows limited positive selection but is associated with proinflammatory cytokine production and autoantibodies. Whether these and other enigmatic outcomes are due to a biochemical uncoupling of tolerogenic signaling, or simply a quantitative reduction of protein activity, remains to be determined. We describe here a splice variant of Lcp2 that reduced the amount of wild-type SLP-76 protein by ~90%, disrupting immunogenic and tolerogenic pathways to different degrees. Mutant mice produced excessive amounts of proinflammatory cytokines, autoantibodies and IgE, revealing that simple quantitative reductions of SLP-76 were sufficient to trigger immune dysregulation. This allele reveals a dose-sensitive threshold for SLP-76 in the balance of immunity and immune dysregulation: a common disturbance of atypical clinical immune deficiencies.

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“…Whole genome and whole exome sequencing as well as copy number analysis will increasingly allow to investigate a large number of rare heterozygote defects, such as modifier genes 93. Indeed, it is very likely that not only the known autosomal dominant loss of function (PTEN, RET) or gain of function mutations (GUCY2C, PLCG2) modify the risk of IBD-like phenotype but that a large group of genes with heterozygous mutations contribute via a gene dosis effects.…”

Section: Rare Variants Causing Ibd-like and Ibd Inflammation: Role Fomentioning

confidence: 99%

Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease

Uhlig

2013

Gut

295

205

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Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, has multifactorial aetiology with complex interactions between genetic and environmental factors. Over 150 genetic loci are associated with IBD. The genetic contribution of the majority of those loci towards explained heritability is low. Recent studies have reported an increasing spectrum of human monogenic diseases that can present with IBD-like intestinal inflammation. A substantial proportion of patients with those genetic defects present with very early onset of intestinal inflammation. The 40 monogenic defects with IBD-like pathology selected in this review can be grouped into defects in intestinal epithelial barrier and stress response, immunodeficiencies affecting granulocyte and phagocyte activity, hyper- and autoinflammatory disorders as well as defects with disturbed T and B lymphocyte selection and activation. In addition, there are defects in immune regulation affecting regulatory T cell activity and interleukin (IL)-10 signalling. Related to the variable penetrance of the IBD-like phenotype, there is a likely role for modifier genes and gene-environment interactions. Treatment options in this heterogeneous group of disorders range from anti-inflammatory and immunosuppressive therapy to blockade of tumour necrosis factor α and IL-1β, surgery, haematopoietic stem cell transplantation or gene therapy. Understanding of prototypic monogenic 'orphan' diseases cannot only provide treatment options for the affected patients but also inform on immunological mechanisms and complement the functional understanding of the pathogenesis of IBD.

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Understanding the immunological impact of the human mutation explosion

Cited by 13 publications

References 71 publications

Targeted Next-Generation Sequencing Successfully Detects Causative Genes in Chinese Patients with Hereditary Hearing Loss

Targeted Next-Generation Sequencing Successfully Detects Causative Genes in Chinese Patients with Hereditary Hearing Loss

Quantitative Reduction of the TCR Adapter Protein SLP-76 Unbalances Immunity and Immune Regulation

Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease

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