Search Results (3)

Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) inflammasomes are multiprotein signaling platforms that control the inflammatory response and coordinate antimicrobial defense. In the present study, the distribution of NLR, Caspase-1, and gasdermin (GSDM) homologues and their structural characteristics and evolutionary relationships were systematically analyzed in metazoa according to the genomes of species. In invertebrates, there were only NLRC and/or NLRD presented from sponge to amphioxus, and according to the evolutionary tree, NLR from sponge located in the most primitive position. Caspase-1 existed in some metazoan phyla (Brachiopoda, Ectoprocta, Arthropoda, Mollusca, Annelia, Nematoda, Platyelminthes, Coelenterate, and Porifera) and its activation sites were relatively conserved. The amino acid sequences and three-dimensional structures of N-terminal CARD/Death domain of NLR and Caspase-1 were similar in species from sponge to human. NLR and Caspase-1 co-existed in species of Brachiopoda, Mollusca, Annelia, Coelenterate, and Porifera. There was only GSDME or PJVK found in some phyla of invertebrates and their cleavage sites were conserved (DxxD). And it was predicted that the NLR inflammasome in inducing pyroptosis could occur in species of Brachiopoda, Mollusca, Annelia, and Coelenterate. These studies indicated that NLR inflammasome emerged early in sponges of metazoa, and NLR inflammasome in inducing pyroptosis first appeared in Coelenterate, suggesting that inflammasome and its mediated pyroptosis had existed in the early stage of metazoa, but they had been lost in many species during evolution. Full article

The genetic etiology of non-syndromic hearing impairment (NSHI) is highly heterogeneous with over 124 distinct genes identified. The wide spectrum of implicated genes has challenged the implementation of molecular diagnosis with equal clinical validity in all settings. Differential frequencies of allelic variants in the most common NSHI causal gene, gap junction beta 2 (GJB2), has been described as stemming from the segregation of a founder variant and/or spontaneous germline variant hot spots. We aimed to systematically review the global distribution and provenance of founder variants associated with NSHI. The study protocol was registered on PROSPERO, the International Prospective Register of Systematic Reviews, with the registration number “CRD42020198573”. Data from 52 reports, involving 27,959 study participants from 24 countries, reporting 56 founder pathogenic or likely pathogenic (P/LP) variants in 14 genes (GJB2, GJB6, GSDME, TMC1, TMIE, TMPRSS3, KCNQ4, PJVK, OTOF, EYA4, MYO15A, PDZD7, CLDN14, and CDH23), were reviewed. Varied number short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs) were used for haplotype analysis to identify the shared ancestral informative markers in a linkage disequilibrium and variants’ origins, age estimates, and common ancestry computations in the reviewed reports. Asia recorded the highest number of NSHI founder variants (85.7%; 48/56), with variants in all 14 genes, followed by Europe (16.1%; 9/56). GJB2 had the highest number of ethnic-specific P/LP founder variants. This review reports on the global distribution of NSHI founder variants and relates their evolution to population migration history, bottleneck events, and demographic changes in populations linked with the early evolution of deleterious founder alleles. International migration and regional and cultural intermarriage, coupled to rapid population growth, may have contributed to re-shaping the genetic architecture and structural dynamics of populations segregating these pathogenic founder variants. We have highlighted and showed the paucity of data on hearing impairment (HI) variants in Africa, establishing unexplored opportunities in genetic traits. Full article

Pathogenic variants in the PJVK gene cause the DFNB59 type of autosomal recessive non-syndromic hearing impairment (AR-NSHI). Phenotypes are not homogeneous, as a few subjects show auditory neuropathy spectrum disorder (ANSD), while others show cochlear hearing loss. The numbers of reported cases and pathogenic variants are still small to establish accurate genotype-phenotype correlations. We investigated a cohort of 77 Spanish familial cases of AR-NSHI, in whom DFNB1 had been excluded, and a cohort of 84 simplex cases with isolated ANSD in whom OTOF variants had been excluded. All seven exons and exon-intron boundaries of the PJVK gene were sequenced. We report three novel DFNB59 cases, one from the AR-NSHI cohort and two from the ANSD cohort, with stable, severe to profound NSHI. Two of the subjects received unilateral cochlear implantation, with apparent good outcomes. Our study expands the spectrum of PJVK mutations, as we report four novel pathogenic variants: p.Leu224Arg, p.His294Ilefs*43, p.His294Asp and p.Phe317Serfs*20. We review the reported cases of DFNB59, summarize the clinical features of this rare subtype of AR-NSHI and discuss the involvement of PJVK in ANSD. Full article