Imagery, encoding, and retrieval of information from memory: some specific encoding--retrieval changes in Huntington's disease.
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Acoustic Stimulation↗
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The adjacent ATP-binding protein-encoding genes of the Enterococcus faecalis phosphate-specific transport (pst) locus have non-overlapping cellular functions.
UNLABELLED: The widely conserved pst-phoU operon encodes a low-velocity, high-affinity, ATP-dependent importer for inorganic phosphate (Pi). The pstB gene encodes the ATPase that powers the import of Pi into the cell. In some Firmicutes, including the gastrointestinal commensal and opportunistic pathogen Enterococcus faecalis, the pst-phoU locus contains adjacent pstB genes. In this work, we compared the functionality of E. faecalis pstB1 and pstB2. E. faecalis pstB1 and pstB2 share sequence similarities with verified PstB ATPases from Escherichia coli and Streptococcus pneumoniae and only share ~60% amino acid identity with each other. Deletion of pstB1 was associated with a growth defect in low Pi-containing chemically defined medium (CDM), reduced Pi uptake, and a moderate increase in alkaline phosphatase (AP) activity. Deletion of pstB2 fully inhibited growth in CDM regardless of inorganic phosphorus source but did not hinder growth in rich, undefined medium. The ΔpstB2 mutant also exhibited a significant increase in AP activity that was associated with extracellular Pi accumulation. Overexpression of pstB2 in the pstB1 mutant was sufficient to restore growth in low-Pi CDM, Pi uptake, and AP activity, but this was not recapitulated with overexpression of pstB1 in the ΔpstB2 mutant. Deletion of either pstB paralog increased expression of the tandem paralog, and overexpression of pstB2 in ΔpstB2 reduced pstB1 expression. These results suggest that the E. faecalis pstB2-encoded ATPase is required for Pi import, while the pstB1-encoded ATPase has an accessory role in Pi import that can be duplicated by the presence of excess PstB2. IMPORTANCE: Phosphate is critical for all microbial life. In many bacteria, inorganic phosphate (Pi) is imported by the high-affinity, low-velocity Pst-PhoU system. The pstB gene encodes the ATPase that powers Pi import. The pst-phoU operon in many Firmicutes, including the human commensal and opportunistic pathogen Enterococcus faecalis, contains adjacent pstB genes, pstB1 and pstB2. No studies on the relative biological contributions of tandem pstB paralogs in any microbe have been published. This genetic study indicates that E. faecalis pstB1 and pstB2 do not have equivalent functions. The pstB2 gene encodes an ATPase that is required for Pi import, while the ATPase encoded by pstB1 has an accessory role in Pi import that can be duplicated by the presence of excess PstB2.
Enterococcus faecalis↗
Emergence of Acinetobacter soli harboring three carbapenemase-encoding genes (blaNDM-1, blaIMP-14, and blaOXA-58) on a single plasmid in an ICU patient.
Acinetobacter soli is an environmentally adaptable species increasingly recognized as an emerging pathogen in hospital settings, particularly in intensive care units (ICUs). In this study, we report the first A. soli isolate from an ICU patient that co-harbors three carbapenemase-encoding genes (blaNDM-1, blaIMP-14, and blaOXA-58) on a single plasmid. Whole-genome sequencing revealed that multidrug resistance in this strain is mediated by a 294,790 bp plasmid, pSLAB-A, carrying 16 antimicrobial resistance genes, including all three carbapenemases. Comparative plasmid analysis showed a highly conserved backbone but identified a unique ~40 kb multidrug-resistance region containing blaNDM-1, blaIMP-14, and eight additional resistance genes. Genetic context analysis indicated that insertion sequences (ISAba125 and ISAba3) and class 1 integrons contribute to the mobilization and accumulation of carbapenemase-encoding genes. Plasmid stability assays demonstrated that pSLAB-A remained stably maintained for more than 90 generations without antibiotic selection. A global survey of the NCBI database identified 15 A. soli strains carrying carbapenemase-encoding genes, most of which were isolated from China, with clinical specimens representing the predominant source. Seven carbapenemase-encoding genes were detected, with blaNDM-1 being the most prevalent. Among eight isolates with complete genomes, all carried carbapenemase-encoding genes on plasmids. Phylogenetic analysis revealed regional dissemination of a clonal lineage across hospitals in Zhejiang Province and sustained nosocomial transmission within a hospital in Taiwan. These findings suggest that the spread of carbapenem resistance in A. soli is largely driven by multidrug-resistance plasmids, facilitating clonal expansion in hospital environments and posing a growing challenge for antimicrobial therapy and infection control in ICUs.IMPORTANCECarbapenem-resistant A. soli is an emerging clinical concern, capable of causing severe invasive infections, including bacteremia, in intensive care unit settings, and its emergence poses substantial challenges to antimicrobial therapy. In this study, we demonstrate that carbapenem resistance in A. soli is predominantly mediated by the acquisition of multidrug-resistance plasmids carrying carbapenemase-encoding genes. Owing to its strong environmental persistence, A. soli can readily undergo nosocomial clonal dissemination once carbapenem resistance is acquired. Moreover, the spread of multidrug plasmids co-harboring multiple carbapenemase-encoding genes may accelerate the evolutionary trajectory of resistance in A. soli, further exacerbating the threat to clinical management. Given its demonstrated capacity to cause hospital-associated infections and to rapidly acquire multidrug resistance, A. soli warrants heightened vigilance from both clinical and public health perspectives.
beta-Lactamases↗
Approaches to Study Proteins Encoded by Essential Genes.
Although the phenotypes and functions of nonessential proteins can be studied by deletion of their coding sequences (both gene copies in diploid organisms), essential genes cannot be deleted unless loss of the encoded protein can be bypassed. Bypass is often achieved by supplementation with the product of the enzyme. However, supplementation cannot bypass loss of essential genes such as those encoding enzymes of DNA or RNA synthesis. To study proteins encoded by essential genes that cannot be bypassed, the mutations must be conditional in nature. The mutant cells must be able to grow under a permissive condition, but fail to grow under a different condition, the nonpermissive condition. Several methods have been developed to obtain conditional mutations in essential genes. Mutations that result in proteins abnormally sensitive to high temperatures are called temperature-sensitive (Ts) mutants and are a widely used type of conditional mutation. An alternative to Ts mutants is the "degron" system to target proteins for destruction by cellular proteases. Approaches to conditionally control the functions of proteins encoded by essential genes, plus the advantages and disadvantages of these and other approaches, will be considered.
Genes, Essential↗
The Salmonella pathogenicity island 1-encoded small RNA InvR mediates post-transcriptional feedback control of the activator HilA in Salmonella.
UNLABELLED: Salmonella Pathogenicity Island 1 (SPI1) encodes a Type-3 secretion system (T3SS) essential for Salmonella invasion of intestinal epithelial cells. Many environmental and regulatory signals control SPI1 gene expression, but in most cases, the molecular mechanisms remain unclear. Many regulatory signals control SPI1 at a post-transcriptional level, and we have identified a number of small RNAs (sRNAs) that control the SPI1 regulatory circuit. The transcriptional regulator HilA activates the expression of the genes encoding the SPI1 T3SS structural and primary effector proteins. Transcription of hilA is controlled by the AraC-like proteins HilD, HilC, and RtsA. The hilA mRNA 5' untranslated region (UTR) is ~350 nucleotides in length and binds the RNA chaperone Hfq, suggesting it is a likely target for sRNA-mediated regulation. We used rGRIL-seq (reverse global sRNA target identification by ligation and sequencing) to identify sRNAs that bind to the hilA 5' UTR. The rGRIL-seq data, along with genetic analyses, demonstrate the SPI1-encoded sRNA invasion gene-associated RNA (InvR) base pairs at a site overlapping the hilA ribosome binding site. HilD and HilC activate both invR and hilA. InvR, in turn, negatively regulates the translation of the hilA mRNA. Thus, the SPI1-encoded sRNA InvR acts as a negative feedback regulator of SPI1 expression. Our results suggest that InvR acts to fine-tune SPI1 expression and prevents overactivation of hilA expression, highlighting the complexity of sRNA regulatory inputs controlling SPI1 and Salmonella virulence. IMPORTANCE: Salmonella Typhimurium infections pose a significant public health concern, leading to illnesses that range from mild gastroenteritis to severe systemic infection. Infection requires a complex apparatus that the bacterium uses to invade the intestinal epithelium. Understanding how Salmonella regulates this system is essential for addressing these infections effectively. Here, we show that the small RNA (sRNA) InvR imposes a negative feedback regulation on the expression of the invasion system. This work underscores the role of sRNAs in Salmonella's complex regulatory network, offering new insights into how these molecules contribute to bacterial adaptation and pathogenesis.
Genomic Islands↗
Hidden proteins encoded by non-canonical open reading frames: A review.
There is increasing evidence that translation is not limited to annotated protein-coding genes. Ribosome profiling sequencing, mass spectrometry-based proteomics, and immunopeptidomics have identified the productive translation of non-canonical open reading frames (ORFs). This suggests that the functional proteome includes not only conserved proteins but also proteins hidden in non-coding RNAs and de novo proteins. Some of these translated products are functional peptides, while others may be non-functional, potentially arising from evolutionary events. Several non-canonical ORF-encoded peptides have been found to regulate multiple physiological and pathological functions, particularly in cancer, immunity, and inflammation, indicating that they have potential as biomarkers and novel therapeutic targets. To better understand the diversity of functional peptides and translated non-canonical ORFs based on existing data, we summarize their classification according to transcriptional features and supporting evidence, including non-canonical ORFs located in ncRNAs and canonical mRNAs. This review provides a concise summary of the origin, discovery methods, and classification of non-canonical ORFs. It offers insights into the origins and functions of non-canonical ORF-encoded peptides from an evolutionary perspective, while also exploring the biological functions and regulatory mechanisms of these non-canonical ORF-encoded hidden proteins in tumorigenesis and progression.
Open Reading Frames↗
Nebulization of an mRNA-encoded monoclonal antibody for passive immunization of foals against Rhodococcus equi.
Inhalation of Rhodococcus equi causes severe pneumonia in humans and animals worldwide, most commonly affecting horse foals. The standard for preventing R. equi pneumonia in foals is transfusion of hyperimmune plasma, which is expensive and carries the risk of adverse effects. Our goal was to passively immunize foals against R. equi by nebulizing mRNA encoding an equine monoclonal antibody (mAb) against the virulence-associated protein A (VapA) directly into the lungs. VapA-specific memory B cells from an immunized horse were used to identify and select the sequence for an equine immunoglobulin (Ig)G1 mAb. In vitro-transcribed mRNA encoding this sequence expressed full-length, VapA-specific mAbs in vitro and safely and effectively produced intrapulmonary mAb in foals for at least 5 days following nebulization. These findings establish a platform to generate mRNA-encoded mAbs for immunotherapeutic and immunoprophylactic applications in horses and demonstrate the feasibility of delivering nebulized mRNA-mAb for intrapulmonary mAb expression in neonates.
Animals↗
A functional atlas of transposon-encoded products and their integration into host networks.
Transposable elements (TEs) are pervasive genomic components that propagate via self-encoded factors, yet the nature, regulation, and function of these factors remain largely unresolved. Here, we integrated extensive long- and short-read transcriptome data, regulatory network analyses, deep proteomics, and structural predictions to construct a comprehensive atlas of TE products in Arabidopsis. We show that TE expression is embedded within host regulatory circuits, with DNA methylation and transcription factors jointly shaping TE transcriptional activity. Proteomic analyses confirm the production of over a hundred of high-confidence TE-encoded proteins, and structure-guided analyses of the transcript-informed TE proteome predict previously uncharacterized structural folds, multimerization capacity, and host protein interaction potential. Structural alignments further uncover cryptic homologies between TE-encoded proteins and host factors, including cases of domestications and co-options. Together, our study reveals the functional integration of TEs into cellular pathways and underscores the role of TEs as active drivers of genome function and innovation.
Arabidopsis↗
Sequences of five potential recombination sites encoded close to an immunoglobulin kappa constant region gene.
Immunoglobulin kappa chain gene formation involves site-specific somatic recombination between one of several hundred germ-line variable region genes and a joining site (or "J segment") encoded close to the constant region gene. We have cloned and determined the nucleotide sequence of major portions of the recombination region of the mouse kappa gene and discovered a series of five such J segments spread out along a segment of DNA 2.4 kilobases from the kappa constant region gene. These J segments encode the 13 COOH-terminal amino acids of the variable region, probably including amino acids involved in the antigen combining site and in heavy/light chain contacts. The J segments also display striking sequence homology to one another in both their coding and immediately flanking sequences. Major elements of a short palindrome--CAC(TA)GTG--are preserved adjacent to the recombination sites of both variable and J region genes and constitute inverted repeats at both ends of the sequences to be joined. These palindromes can be written as a hypothetical stem structure that draws variable and J regions together, providing a possible molecular basis for the DNA joining event. Four of the J segments that we have discovered encode amino acid sequences already found in myeloma proteins. By altering the frame of recombination, we can account for additional light chain amino acid sequences, suggesting that the V/J joining event might generate antibody diversity somatically both by using different combinations of variable and J region genes and by using alternative joining frames.
Animals↗
Micropeptides encoded by lncRNAs associated with cancer progression reveal novel immunogenic epitopes.
MOTIVATION: Long non-coding RNAs (lncRNAs) regulate gene expression, chromatin organization, and cellular signaling. Recent studies indicate that ∼20% of the ∼36 000 human lncRNA genes harbor small open reading frames (sORFs) capable of producing micropeptides (MPs), whose functions remain largely unknown. Whether these peptides contribute to the cancer immunopeptidome is largely unexplored. RESULTS: We systematically analyzed lncRNAs with strong experimental and computational evidence of MP-encoding potential (∼13% of the initial MP collection). Using The Cancer Genome Atlas (TCGA), we identified 2606 high-confidence lncRNA-derived MPs encoded by 647 genes across 16 cancer types. We then focused on 501 MPs from 124 lncRNA genes whose expression changes significantly across tumor stages and metastatic transitions, representing cancer transitional lncRNAs (Tr-lncRNAs). Dipeptide composition and conservation analyses showed that these MPs differ from a size-matched human coding proteome, supporting their potential as neoantigens. All possible 9-mer peptides were evaluated for predicted binding to prevalent European HLA class I alleles. Approximately 60% of Tr-lncRNA genes and 184 (37%) of derived peptides exhibited strong predicted HLA binding. Peptides from XIST, PCAT7, PVT1, HAND2-AS1 showed broad HLA coverage. Notably, TTN-AS1, encoded an MP (79 aa) generated 33 predicted distinct epitopes spanning all 27 HLA alleles. Our analysis identifies lncRNA-derived MPs as a previously underexplored source of potential cancer neoantigens, highlighting their promise as biomarkers and targets for immunotherapy. AVAILABILITY: Data, code and supplementary materials are available in https://doi.org/10.5281/zenodo.20167452 and GitHub: https://github.com/stavzok1/lncrna_peptide_analysis.
Humans↗
Staphylococcus aureus Prophage-Encoded Protein Causes Abortive Infection and Provides Population Immunity against Kayviruses.
Both temperate and obligately lytic phages have crucial roles in the biology of staphylococci. While superinfection exclusion among closely related temperate phages is a well-characterized phenomenon, the interactions between temperate and lytic phages in staphylococci are not understood. Here, we present a resistance mechanism toward lytic phages of the genus Kayvirus, mediated by the membrane-anchored protein designated PdpSau encoded by Staphylococcus aureus prophages, mostly of the Sa2 integrase type. The prophage accessory gene pdpSau is strongly linked to the lytic genes for holin and ami2-type amidase and typically replaces genes for the toxin Panton-Valentine leukocidin (PVL). The predicted PdpSau protein structure shows the presence of a membrane-binding α-helix in its N-terminal part and a cytoplasmic positively charged C terminus. We demonstrated that the mechanism of action of PdpSau does not prevent the infecting kayvirus from adsorbing onto the host cell and delivering its genome into the cell, but phage DNA replication is halted. Changes in the cell membrane polarity and permeability were observed from 10 min after the infection, which led to prophage-activated cell death. Furthermore, we describe a mechanism of overcoming this resistance in a host-range Kayvirus mutant, which was selected on an S. aureus strain harboring prophage 53 encoding PdpSau, and in which a chimeric gene product emerged via adaptive laboratory evolution. This first case of staphylococcal interfamily phage-phage competition is analogous to some other abortive infection defense systems and to systems based on membrane-destructive proteins. IMPORTANCE Prophages play an important role in virulence, pathogenesis, and host preference, as well as in horizontal gene transfer in staphylococci. In contrast, broad-host-range lytic staphylococcal kayviruses lyse most S. aureus strains, and scientists worldwide have come to believe that the use of such phages will be successful for treating and preventing bacterial diseases. The effectiveness of phage therapy is complicated by bacterial resistance, whose mechanisms related to therapeutic staphylococcal phages are not understood in detail. In this work, we describe a resistance mechanism targeting kayviruses that is encoded by a prophage. We conclude that the defense mechanism belongs to a broader group of abortive infections, which is characterized by suicidal behavior of infected cells that are unable to produce phage progeny, thus ensuring the survival of the host population. Since the majority of staphylococcal strains are lysogenic, our findings are relevant for the advancement of phage therapy.
Humans↗
Bacillus thuringiensis pathogenicity islands encode regulatory circuits controlling insecticidal Cry toxin expression during vegetative growth.
Bacillus thuringiensis (Bt) produces insecticidal toxins, including Cry and Vip3 proteins, that are widely used for biological pest control. Cry proteins are classically expressed during sporulation under the control of sporulation-specific σ factors, whereas Vip3 is produced during vegetative growth, suggesting distinct regulatory pathways. Notably, many cry and vip3A genes are clustered within pathogenicity islands (PAIs), such as BtPAI-1. However, whether these PAIs also encode regulatory mechanisms coordinating toxin expression remains unclear. Here, we identify VipR, a BtPAI-1-encoded transcriptional regulator, as an activator of insecticidal gene expression during the vegetative phase in Bt strains HD-1 and CT-43. In these strains, VipR promotes the transcription of BtPAI-1 associated insecticidal genes, including vip3A and selected cry genes, resulting in premature Cry protein accumulation and increased insecticidal activity. In addition, VipR contributes to the vegetative-phase expression of the non-BtPAI-1 cry9Aa genes in strain BGSC 4AE1. Phylogenetic analysis revealed that vipR is widely distributed in one-third of Bt strains, and is strongly associated with PAIs. Futhermore, heterologous expression of vipR in BGSC 4J5 and HD-73 was sufficient to activate vegetative-phase transcription of some cry independently of sporulation-specific σ factor cascade. These results support a role for VipR in coordinating vegetative-phase expression of insecticidal genes in the Bt strains examined and suggest that BtPAI-1 can encode both insecticidal determinants and regulatory functions that influence their expression. These findings provide new insights into the regulatory architecture of Bt pathogenicity islands and may facilitate the engineering of strains with enhanced insecticidal activity.
Bacillus thuringiensis↗
Phage-encoded sRNA counteracts xenogeneic silencing in pathogenic E. coli.
Horizontal gene transfer introduces foreign DNA that can disrupt cellular processes and is therefore subject to xenogeneic silencing by nucleoid-associated proteins such as H-NS and Hha. In Enterohaemorrhagic Escherichia coli (EHEC), prophages make up a large fraction of the accessory genome and encode many virulence factors, yet their expression must overcome this silencing. We identify a prophage-encoded small RNA (sRNA), HnrS, that functions as an anti-silencing factor by targeting the H-NS paralogue Hha. HnrS is a short (66-nt) sRNA that is enriched in the locus of enterocyte effacement (LEE⁺) E. coli strains and present in up to nine copies in EHEC and Enteropathogenic Escherichia coli (EPEC) genomes. HnrS base-pairs with the hha ribosome-binding site to inhibit translation, thereby modulating Hha-H-NS repression of virulence loci including the LEE type III secretion system. Loss of HnrS alters motility, T3SS expression, and a subset of Hha-regulated genes. These findings reveal an RNA-based counter-silencing strategy encoded by prophage to relieve xenogenic silencing.
Escherichia coli Proteins↗
Non-coding regions of nuclear-DNA-encoded mitochondrial genes and intergenic sequences are targeted by autoantibodies in breast cancer.
Autoantibodies against mitochondrial-derived antigens play a key role in chronic tissue inflammation in autoimmune disorders and cancers. Here, we identify autoreactive nuclear genomic DNA (nDNA)-encoded mitochondrial gene products (GAPDH, PKM2, GSTP1, SPATA5, MFF, TSPOAP1, PHB2, COA4, and HAGH) recognized by breast cancer (BC) patients' sera as nonself, supporting a direct relationship of mitochondrial autoimmunity to breast carcinogenesis. Autoreactivity of multiple nDNA-encoded mitochondrial gene products was mapped to protein-coding regions, 3' untranslated regions (UTRs), as well as introns. In addition, autoantibodies in BC sera targeted intergenic sequences that may be parts of long non-coding RNA (lncRNA) genes, including LINC02381 and other putative lncRNA neighbors of the protein-coding genes ERCC4, CXCL13, SOX3, PCDH1, EDDM3B, and GRB2. Increasing evidence indicates that lncRNAs play a key role in carcinogenesis. Consistent with this, our findings suggest that lncRNAs, as well as mRNAs of nDNA-encoded mitochondrial genes, mechanistically contribute to BC progression. This work supports a new paradigm of breast carcinogenesis based on a globally dysfunctional genome with altered function of multiple mitochondrial and non-mitochondrial oncogenic pathways caused by the effects of autoreactivity-induced dysregulation of multiple genes and their products. This autoimmunity-based model of carcinogenesis will open novel avenues for BC treatment.
autoimmunity↗
Male and Female Mice Show Similar Fear Memory Performance Despite Hippocampal Immediate Early Gene Expression Differences During Encoding and Consolidation.
Accurate and efficient memory processing is essential for survival. A body of ongoing work in both human subjects and animal models suggests that memory processing may differ substantially between males and females. In mice, contextual fear memory (CFM) encoding, consolidation, and recall have been well studied, and the mouse hippocampus and amygdala have been implicated in these processes. The present pilot study addresses whether the activation of these brain regions differs substantially between male and female mice at each stage of CFM processing. We find that male and female mice show no differences in sleep behavior, which is essential for CFM consolidation, following single-trial contextual fear conditioning (CFC). We also find no significant differences in CFM recall performance between male and female mice. However, females show a trend for larger increases in CA1 cFos expression, relative to males, during CFM encoding. On the other hand, only males-but not females-show an apparent increase in cFos expression among dentate gyrus (DG) granule cells during CFM consolidation. Males also show a trend for a larger apparent reduction in cFos in CA1 and CA3 during CFM consolidation, relative to females. These preliminary findings highlight the idea that the neurobiological underpinnings of memory processing may differ between males and females, even when performance during recall is identical.
Animals↗
Constitutive expression in Escherichia coli of the Neurospora crassa structural gene encoding the inducible enzyme catabolic dehydroquinase.
In Neurospora crassa the qa-2 gene, which encodes catabolic dehydroquinase, is under positive control exerted by the inducer quinic acid and an activator protein encoded in the closely linked qa-1 gene. In order to determine if this regulatory mechanism is maintained when the qa-2 gene is cloned on a recombinant plasmid and expressed in Escherichia coli, molecular cloning experiments have been performed using DNA isolated from a qa-1+ (inducible), a qa-1C (constitutive) and two qa-1 (non-inducible) strains of N. crassa. The results demonstrate that the level of expression of the qa-2 gene in E. coli is completely independent of the mutational state of the qa-1 gene. Moreover, the level of expression of the cloned qa-2 gene was unaffected by either an intracellularly produced inducer of catabolic dehydroquinase or by the general procaryotic positive effector, the CAP factor. The weight of evidence thus supports the conclusion that transcription of the N. crassa qa-2 gene in E. coli does not require the qa-1 activator protein and thus is not controlled by the same mecahnism which functions in N. crassa.
Centrifugation, Density Gradient↗
An optical scan system for encoding and tabulation of visually scored sleep data.
A system for computer-assisted encoding, tabulation and analysis of visually scored sleep data is presented. The main features of the system are: (1) The use of computer-readable optical scan sheets for direct encoding of the sleep data. This eliminates the need for a separate transcription and/or key-punching operation. (2) The development of a visually scored data base, organized by NREM and REM periods, which contains all items of visually scored data indexed by time and/or page of occurrence in the sleep record. The advantages of this new system are: (a) the low cost per night of operation; (b) the facilitation of analysis of cycle phenomena and testing of new hypotheses that would usually involve retabulation of the data; and (c) the facilitation of analysis of real-time correlates of visually scored sleep stages.
Computers↗
Identification of IDH3G, encoding the gamma subunit of mitochondrial isocitrate dehydrogenase, as a novel candidate gene for X-linked retinitis pigmentosa.
PURPOSE: Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerative disorders characterized by the loss of rod and cone photoreceptors, leading to visual impairment and blindness. To date, to our knowledge, X-linked RP has been associated with variants in 3 genes (RPGR, RP2, and OFD1), whereas genetic defects at 3 loci (RP6, RP24, and RP34) are yet unidentified. The aim of this study was to identify a novel candidate gene underlying X-linked RP. METHODS: Participants were identified from cohorts of genetically unsolved male individuals affected by RP, who underwent genome sequencing, exome sequencing, or candidate gene screening via direct Sanger sequencing at 3 referral centers. Specifically, 2 probands were identified at the National Reference Centre for Rare Retinal Diseases (Paris, France), 2 at the Massachusetts Eye and Ear Hospital (Boston, MA), and 1 at the National Reference Centre for Inherited Sensory Diseases (Montpellier, France). The pathogenicity of the identified variants was assessed using bioinformatic predictions, protein expression analyses, and mitochondrial function assays. RESULTS: We identified 4 rare single-nucleotide variants in IDH3G (HGNC:5386), located at the RP34 locus on the X chromosome, and a complete gene deletion, in 5 unrelated male individuals affected with nonsyndromic RP. The variants segregated with the phenotype in all available family members. In all cases, the disease severity was intermediate. None had high myopia. IDH3G encodes the γ subunit of mitochondrial isocitrate dehydrogenase (IDH3), an enzyme involved in the citric acid cycle, which is expressed in the inner segments of photoreceptors. Variants in IDH3A and IDH3B, encoding the other subunits of IDH3, have already been associated with nonsyndromic autosomal recessive RP. Bioinformatic predictions and functional assays support a pathogenic role for the variants identified in this study, possibly through partial loss of enzymatic activity and mitochondrial function. CONCLUSION: Our findings suggest that variants in IDH3G are a novel cause of X-linked RP.
Humans↗