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The inherited basis of hypergonadotropic hypogonadism
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
The hypothesis that mutations in genes encoding a broader range of modulators of the FGFR1 pathway might contribute to the genetics of CIHH as causal or modifier has been tested in a large group of IHH individuals and has revealed that mutations in members of the so-called FGF8 synexpression group, namely FGF17, IL17RD, DUSP6, SPRY4, and FLRT3, harbor potential loss-of-function mutations in CIHH patients.80 On the basis of their protein–protein interaction patterns with proteins known to be altered in CIHH, FGF17 and IL17RD were predicted to be potentially important genes in IHH. Most of the FGF17 and IL17RD mutations altered protein function in vitro. IL17RD mutations were found only in KS individuals and were strongly linked to hearing loss (six of eight individuals). Mutations in genes encoding components of the FGF pathway were found to be associated with complex modes of CIHH inheritance acting primarily as contributors to an oligogenic genetic architecture underlying CIHH.
Multifaceted Role of Th17 Cells in Psoriatic Disease
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
IL-17A (also known as IL-17) is a glycoprotein member of the larger family of IL-17 cytokines, namely IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. IL-17A most closely relates to IL-17F, with these isoforms resulting in the formation of homodimers or heterodimers. Additionally, IL-17C acts in an autocrine manner and its functions overlap with those of IL-17A [12]. IL-17 is the hallmark cytokine produced by Th17 cells, but notably, αβ CD8+ T cells, innate lymphoid cells type 3 (ILC3s), γδ T cells, NK-T cells, mast cells, and neutrophils can also produce IL-17 as a homodimer or heterodimer with IL-17F. The IL-17 receptor family has five members: IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE [9]. IL-17A (in addition to IL-17F) binds its receptor IL-17R (IL-17RA/IL-17RC heterodimer), which is found on the cellular surface of monocytes, keratinocytes, fibroblasts, epithelial cells, and synoviocytes. This triggers the recruitment of nuclear factor κB (NFκB) activator 1 (ACT1) adaptor protein, which in turn activates mitogen-activated protein kinases (MAPKs), such as p38 MAPK. Other signaling pathways, involving c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), Janus kinase (JAK), signal transducer and activator of transcription 3 (STAT3), and phosphoinositol 3 kinase (PI3K), can also be activated [9]. In epithelial and other parenchymal cells, IL-17R activation induces a wide array of pro-inflammatory mediators, such as IL-1, IL-6, IL-8, TNFα, G-CSF, and matrix metalloproteinases (MMPs), thereby causing host tissue to become more pliant to cellular infiltration and tissue inflammation [9]. IL-6 is involved in the development of a febrile response, G-CSF leads to the expansion of neutrophilic lineages, and IL-8 enhances neutrophil migration to the involved tissues [13].
Identification of novel genes by targeted exome sequencing in Retinoblastoma
Published in Ophthalmic Genetics, 2022
Shilpa Bisht, Bhavna Chawla, Amit Kumar, Viswanathan Vijayan, Manoj Kumar, Pradeep Sharma, Rima Dada
ARL11 encodes for a tumor suppressor gene related to the ADP-ribosylation factor (ARF) family of proteins (57). ARL11 protein plays an essential role in apoptosis in a caspase-dependent manner. Polymorphisms in ARL11 are found to be associated with some forms of familial cancers (58). Down-regulation of ARL11 expression in several sporadic lung cancer and ovarian tumors attributed to promoter methylation and loss of heterozygosity (LOH) at the ARL11 locus (57). Although the direct role of ARL11 mutation has not been described in RB pathogenesis, but in our study, we have found ARL11: g.2595G>A (nonsense mutation) in 4 RB patients which showed a significant contribution of the loss-of-function of tumor suppressor genes present in the 13q14.2 (location of RB1 tumor suppressor gene also) region. The actual mechanism of how ARL11 loss-of-function might contribute to RB progression is not known. But we might predict that ARL11 mediates its function through regulation of its downstream target genes (ADAM17, HIF1AN, IL17RD, and ALDH3A2) that have important role on tumorigenesis regulation. Hence, further extensive studies are required to determine the role of other genes present in the 13q14.2 locus so as to determine their essential functions in RB pathogenesis.
Role of IL-17 in asthma pathogenesis and its implications for the clinic
Published in Expert Review of Respiratory Medicine, 2019
Rakhee K Ramakrishnan, Saba Al Heialy, Qutayba Hamid
IL-17 cytokine family includes six members – IL-17A, B, C, D, E and F [17], of which IL-17A and IL-17F are the classical cytokines associated with Th17 cells. IL-17A and IL-17F are known to induce the local production of cytokines, chemokines, granulopoietic factors, antimicrobial peptides and metalloproteinases that are responsible for the recruitment, activation as well as migration of neutrophils [18]. IL-17 signaling operates via multiple cognate receptors, including IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE [19]. IL-17A and IL-17F have their respective cognate cytokine receptors of IL-17RA, highly expressed in hematopoietic cells and also found in non-hematopoietic cells like epithelial cells, endothelial cells, fibroblasts, and osteoblasts to a lesser extent [20], and IL-17RC, highly expressed in non-hematopoietic cells with low expression seen in hematopoietic cells [21], respectively. IL-17A and IL-17F can also mediate their effects through the heterodimer receptor complex composed of IL-17RA and IL-17RC. The diverse cellular distribution of IL-17R supports the wide pleiotropic effects of IL-17. Besides IL-17A and IL-17F, Th17 cells also produce cytokines such as IL-21 and IL-22.