Congenital anomalies of kidney and urinary tract (CAKUT), including vesico-ureteric reflux (VUR), are major causes of ESRD in childhood. Herein is reported evidence for a locus on 13q33q34 associated with CAKUT. Deletion mapping of chromosome 13q was performed in four children with CAKUT using 31 microsatellite markers on peripheral blood genomic DNA that was obtained from the patients and their parents. mRNA expression of the positional candidate genes was compared with sequences in electronic databases in silico and also studied in adult and fetal mouse kidneys using reverse transcription-PCR. The children (three girls; age range 5 to 17 yr) had varying severity of developmental delay and other organ system involvement. The spectrum of CAKUT included high-grade VUR (n ؍ 2), renal dysplasia (n ؍ 2), and hydronephrosis (n ؍ 1). Both the children with VUR had evidence of renal failure with one of them developing ESRD. Deletion mapping identified a 7-Mb critical region flanked by markers D13S1311 and D13S285. There are 33 genes (12 known; 21 computer predicted) in this region. In silico expression studies showed matches for 14 of these genes in the kidneys and 10 in the bladder expressed sequenced tags databases. Mouse kidney studies showed that of the 24 genes examined, several had variable expression through the different stages of renal development, whereas five of the genes were not expressed at all. Herein is reported a new locus on chromosome 13q33q34 that can be associated with VUR with several genes showing mRNA expression patterns that suggest their potential for involvement in renal/urinary tract developmental anomalies.
Inflammasomes are multiprotein caspase-activating complexes that enhance the maturation and release of proinflammatory cytokines (IL-1β and IL-18) in response to the invading pathogen and/or host-derived cellular stress. These are assembled by the sensory proteins (viz NLRC4, NLRP1, NLRP3, and AIM-2), adaptor protein (ASC), and effector molecule procaspase-1. In NLRP3-mediated inflammasome activation, ASC acts as a mediator between NLRP3 and procaspase-1 for the transmission of signals. A series of homotypic protein-protein interactions (NLRP3 :ASC and ASC :CASP1 ) propagates the downstream signaling for the production of proinflammatory cytokines. Pyrin-only protein 1 (POP1) is known to act as the regulator of inflammasome. It modulates the ASC-mediated inflammasome assembly by interacting with pyrin domain (PYD) of ASC. However, despite similar electrostatic surface potential, the interaction of POP1 with NLRP3 is obscured till date. Herein, to explore the possible PYD-PYD interactions between NLRP3 and POP1, a combined approach of protein-protein docking and molecular dynamics simulation was adapted. The current study revealed that POP1's type-Ia interface and type-Ib interface of NLRP3 might be crucial for 1:1 PYD-PYD interaction. In addition to type-I mode of interaction, we also observed type-II and type-III interaction modes in two different dynamically stable heterotrimeric complexes (POP1-NLRP3-NLRP3 and POP1-NLRP3-POP1). The inter-residual/atomic distance calculation exposed several critical residues that possibly govern the said interaction, which need further investigation. Overall, the findings of this study will shed new light on hitherto concealed molecular mechanisms underlying NLRP3-mediated inflammasome, which will have strong future therapeutic implications.
BackgroundALRs (AIM2-like Receptors) are germline encoded PRRs that belong to PYHIN gene family of cytokines, which are having signature N-terminal PYD (Pyrin, PAAD or DAPIN) domain and C-terminal HIN-200 (hematopoietic, interferon-inducible nuclear protein with 200 amino acid repeat) domain joined by a linker region. The positively charged HIN-200 domain senses and binds with negatively charged phosphate groups of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) purely through electrostatic attractions. On the other hand, PYD domain interacts homotypically with a PYD domain of other mediators to pass the signals to effector molecules downwards the pathways for inflammatory responses. There is remarkable inter-specific diversity in the numbers of functional PYHIN genes e.g. one in cow, five in human, thirteen in mice etc., while there is a unique loss of PYHIN genes in the bat genomes which was revealed by Ahn et al. (2016) by studying genomes of ten different bat species belonging to sub-orders yinpterochiroptera and yangochiroptera. The conflicts between host and pathogen interfaces are compared with “Red queen’s arms race” which is also described as binding seeking dynamics and binding avoidance dynamics. As a result of this never-ending rivalry, eukaryotes developed PRRs as antiviral mechanism while viruses developed counter mechanisms to evade host immune defense. The PYHIN receptors are directly engaged with pathogenic molecules, so these should have evolved under the influence of selection pressures. In the current study, we investigated the nature of selection pressure on different domain types of IFI16-like (IFI16-L) PYHIN genes in ruminants.ResultsThree transcript variants of the IFI16-like gene were found in PBMCs of ruminant animals-water buffalo, zebu cattle, goat, and sheep. The IFI16-like gene has one N-terminal PYD domain and one C-terminal HIN-200 domain, separated by an inter-domain linker region. HIN domain and inter-domain region are positively selected while the PYD domain is under the influence of purifying selection.ConclusionHerein, we conclude that the nature of selection pressure varies on different parts (PYD domain, HIN domain, and inter-domain linker region) of IFI16-like PYHIN genes in the ruminants. This data can be useful to predict the molecular determinants of pathogen interactions.Electronic supplementary materialThe online version of this article (10.1186/s12862-018-1334-7) contains supplementary material, which is available to authorized users.
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