Biology subjects

Li, C.

Publications and source records attributed to Li, C..

At least 991 records · Page 55Linked to original sources

bioRxiv2019

Elucidation of the determinant for orchestration of solo unisexual cycle in an important human fungal pathogen

In fungi, the sex-determination program universally directs sexual development and syngamy (the fusion of gametes) that underlies pre-meiotic diploidization. However, the contribution of sex-determination to syngamy-independent sexual cycle, which requires autopolyploidization as an alternative approach to elevate ploidy before meiosis, remains unclear in fungi and other eukaryotes. The human fungal pathogen Cryptococcus neoformans, as a model organism for studying fungal sexual reproduction, can undergo syngamy-dependent bisexual and syngamy-independent solo unisexual reproduction, in which endoreplication is considered to enable pre-meiotic self-diploidization. Here, by characterizing a mutant lacking all the core sex-determination factors, we show that sex-determination plays a central role in bisexual syngamy but is not strictly required for unisexual development and self-diploidization. This implies an unknown circuit, rather than the sex-determination program, for specifically coordinating Cryptococcus unisexual cycle. We reveal that syngamy and self-diploidization are both governed by the Qsp1-directed paracrine system via two regulatory branches, Vea2 and Cqs2. Vea2 directs bisexual syngamy through the sex-determination program; conversely, Cqs2 is dispensable for bisexual syngamy but activates unisexual endoreplication. Through functional profiling of 41 transcription factors documented to regulate Cryptococcus sexual development, we reveal that only Cqs2 can drive and integrate all unisexual phases and ensure the production of meiospore progenies. Furthermore, ChIP-seq analysis together with genetic evaluation indicate that Cqs2 induces unisexual self-diploidization through its direct control of PUM1, whose expression is sufficient to drive autopolyploidization. Therefore, Cqs2 serves as the critical determinant that orchestrates Cryptococcus multistage unisexual cycle that does not strictly require the sexual-determination program.

microbiology↗

bioRxiv2019

Signaling compartment at the ciliary tip is formed and maintained by intraflagellar transport and functions as sensitive salt detector

Primary cilia are ubiquitous antenna-like organelles that mediate cellular signaling and represent hotspots for human diseases termed ciliopathies. How signaling subcompartments are established within the microtubule-based organelle, and for example support Hedgehog or cGMP signal transduction pathways, remains a central question. Here we show that a C. elegans salt-sensing receptor type guanylate cyclase, GCY-22, accumulates at a high concentration within the distal region of the cilium. This receptor uses DAF-25 (Ankmy2 in mammals) to cross the transition zone (TZ) membrane diffusion barrier in the proximal-most region of the ciliary axoneme. Targeting of GCY-22 to the ciliary tip is dynamic, requiring the cargo-mobilizing intraflagellar transport (IFT) system. Disruption of transit across the TZ barrier or IFT trafficking causes GCY-22 protein mislocalization and defects in the formation, maintenance, and function of the ciliary tip compartment required for chemotaxis to low NaCl concentrations. Together, our findings reveal how a previously undescribed cilium tip cGMP signaling compartment is established and contributes to the physiological function of a primary cilium.

cell biology↗

bioRxiv2019

Identification of Genomic Insertion and Flanking Sequences of the Transgenic Drought-tolerant Maize Line "SbSNAC1-382" using the Single Molecular Real-Time (SMRT) Sequencing Method

Safety assessment of genetically modified (GM) crops is crucial in the phase of product development before the GM crops are put on the market. Characteristics of flanking sequences of exogenous insertion sequences are essential for the safety assessment and marking of transgenic crops. In this study, we used the methods of genome walking and whole genome sequencing (WGS) to identify the flanking sequence characteristics of a SbSNAC1 transgenic drought-tolerant maize line "SbSNAC1-382", but both of the methods failed. Then, we constructed a genomic fosmid library of the transgenic maize line, which contained 4.18x105 clones with an average insertion fragment of 35 kb, covering 5.85 times of the maize genome. Subsequently, three positive clones were screened by pairs of specific primers and one of the three positive clones was sequenced by using the Single Molecule Real-Time (SMRT) sequencing technology. More than 1.95 Gb sequence data ([~]105 x coverage) for the sequenced clone was generated. The junction reads mapped to the boundaries of T-DNA and the flanking sequences in the transgenic line were identified by comparing all sequencing reads with the maize reference genome and the sequence of transgenic vector. Furthermore, the putative insertion loci and flanking sequences were confirmed by PCR amplification and Sanger sequencing. The results indicated that two copies of the exogenous T-DNA fragments were inserted in the same genomic site. And the exogenous T-DNA fragments were integrated at the position of Chromosome 5: 177155650 to 177155696 in the transgenic line 382. Herein, we have demonstrated the successful application of the SMRT technology for the characterization of genomic insertion and flanking sequences.

molecular biology↗

bioRxiv2019

The microRNA476a/RFL module regulates adventitious root formation through a mitochondria-dependent pathway in Populus

Adventitious root (AR) formation at the base of stem cuttings determines the efficiency of clonal propagation for woody plants. Many endogenous and environmental factors influence AR formation. However, our knowledge about the regulation of AR development by mitochondrial metabolism in plants is very limited. Here we identified Populus-specific miR476a as a novel regulator of wound-induced adventitious rooting via orchestrating mitochondrial homeostasis in poplar. MiR476a exhibited inducible expression during AR formation and directly targets several Restorer of Fertility like (RFL) genes encoding mitochondrion-localized pentatricopeptide repeat proteins. Genetic modification of miR476-RFL expression revealed the miR476/RFL-mediated dynamic regulation of mitochondrial homeostasis on AR formation in transgenic poplar. Furthermore, mitochondrial perturbation via exogenous chemical inhibitor validated that the miR476a/RFL-directed AR formation depended on mitochondrial regulation though modulating the auxin pathway. Our results established a miRNA-directed mitochondrion-auxin signaling cascade required for AR development, providing novel insights into the understanding of mitochondrial regulation on plant developmental plasticity.

plant biology↗

bioRxiv2019

Variation in the life history strategy of cells underlies tumor’s functional diversity

Classical r- vs. K-selection theory describes the trade-offs between high reproductive output and competitiveness and guides research in evolutionary ecology1-5. While its impact has waned in the recent past, cancer evolution may rekindle it6-10. Indeed, solid tumors are an ideal theater for r- and K-selection and, hence, a good testing ground for ideas on life-history strategy evolution11,12. In this study, we impose r- or K-selection on HeLa cells to obtain strongly proliferative r cells and highly competitive K cells. RNA-seq analysis indicates that phenotypic trade-offs in r and K cells are associated with distinct patterns of expression of genes involved in the cell cycle, adhesion, apoptosis, and contact inhibition. Both empirical observations and simulations based on an ecological competition model show that the trade-off between cell proliferation and competitiveness can evolve adaptively and rapidly in naive cell lines. It is conceivable that the contrasting selective pressure may operate in a realistic ecological setting of actual tumors. When the r and K cells are mixed in vitro, they exhibit strikingly different spatial and temporal distributions in the resultant cultures. Thanks to this niche separation, the fitness of the entire tumor increases. Our analyses of life-history trade-offs are pertinent to evolutionary ecology as well as cancer biology.

evolutionary biology↗

bioRxiv2019

Cross-kingdom regulation of tRNAs/tRFs derived from Chinese yew

Plants containing countless chemical constituent have benefited mankind since the origin of life. Although secondary metabolites in plants, such as morphine, artemisinin and taxol, have been developed as therapeutic drugs for clinical therapy, few study focuses on the pharmacological activities of plant small RNAs with function of cross-kingdom regulations. Yew is widely considered as a \"superstar\" plant due to the discovery of paclitaxel, or taxol, which is a well-known natural drug for the treatment of multiple types of cancer1. Here we show the surprising finding that an RNA fragment, named tRF-T11, derived from tRNAHis(GUG) of Chinese yew strongly suppressed human ovarian cancer progression. In A2780 cells, tRF-T11 mimic (a double-stranded RNA with tRF-T11 as antisense chain) exhibited potent cytotoxicity comparable to that of taxol, but no significant cytotoxicity to normal ovarian surface epithelial cells. Moreover, the cytotoxicity of tRF-T11 mimic is 80-fold stronger than that of taxol in taxol-resistant A2780 cells. Bioinformatic and molecular biological studies revealed that tRF-T11 targets transient receptor potential cation channel subfamily A member 1 (TRPA1) to inhibit its expression levels. In a further in vivo investigation, the growth rate of ovarian tumor xenografts in nude mice was significantly reduced by treatment with tRF-T11 mimic, and the TRPA1 protein expression in tumors treated with tRF-T11 mimic was also down-regulated. Our findings are the first to provide evidence that plant-derived tRFs can regulate the expression of target genes in vitro and in vivo, indicating that they may become as a new source of druggable siRNA. Moreover, this discovery demonstrated a pilot example of an innovative approach for not only identifying pharmacologically-active tRFs from plants, but also for improving the efficiency and possibilities of discovering new drug target.

cell biology↗

bioRxiv2019

ROGUE: an entropy-based universal metric for assessing the purity of single cell population

Single-cell RNA sequencing (scRNA-seq) is a versatile tool for discovering and annotating cell types and states, but the determination and annotation of cell subtypes is often subjective and arbitrary. Often, it is not even clear whether a given cluster is uniform. Here we present an entropy-based statistic, ROGUE, to accurately quantify the purity of identified cell clusters. We demonstrated that our ROGUE metric is generalizable across datasets, and enables accurate, sensitive and robust assessment of cluster purity on a wide range of simulated and real datasets. Applying this metric to fibroblast and B cell datasets, we identified additional subtypes and demonstrated the application of ROGUE-guided analyses to detect true signals in specific subpopulations. ROGUE can be applied to all tested scRNA-seq datasets, and has important implications for evaluating the quality of putative clusters, discovering pure cell subtypes and constructing comprehensive, detailed and standardized single cell atlas.

bioinformatics↗

bioRxiv2019

Mechanistic insights into NAD synthase NMNAT chaperoning phosphorylated Tau from pathological aggregation

Tau hyper-phosphorylation and deposition into neurofibrillary tangles have been found in brains of patients with Alzheimers disease (AD) and other tauopathies. Molecular chaperones are involved in regulating the pathological aggregation of phosphorylated Tau (pTau) and modulating disease progression. Here, we report that nicotinamide mononucleotide adenylyltransferase (NMNAT), a well-known NAD synthase, serves as a chaperone of pTau to prevent its amyloid aggregation in vitro as well as mitigate its pathology in a fly tauopathy model. By combining NMR spectroscopy, crystallography, single-molecule and computational approaches, we revealed that NMNAT adopts its enzymatic pocket to specifically bind the phosphorylated sites of pTau, which can be competitively disrupted by the enzymatic substrates of NMNAT. Moreover, we found that NMNAT serves as a co-chaperone of Hsp90 for the specific recognition of pTau over Tau. Our work uncovers a dedicated chaperone of pTau and suggests NMNAT as a key node between NAD metabolism and Tau homeostasis in aging and neurodegeneration.

biochemistry↗

bioRxiv2019

Single-cell transcriptome profiling reveals neutrophil heterogeneity and orchestrated maturation during homeostasis and bacterial infection

The full neutrophil heterogeneity and differentiation landscape remains incompletely characterized. Here we profiled >25,000 differentiating and mature mouse neutrophils using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of neutrophil maturation, function, and fate decision in their steady state and during bacterial infection. Eight neutrophil populations were defined by distinct molecular signatures. The three mature peripheral blood neutrophil subsets arise from distinct maturing bone marrow neutrophil subsets. Driven by both known and uncharacterized transcription factors, neutrophils gradually acquire microbicidal capability as they traverse the transcriptional landscape, representing an evolved mechanism for fine-tuned regulation of an effective but balanced neutrophil response. Bacterial infection reprograms the genetic architecture of neutrophil populations, alters dynamic transition between each subpopulation, and primes neutrophils for augmented functionality without affecting overall heterogeneity. In summary, these data establish a reference model and general framework for studying neutrophil-related disease mechanisms, biomarkers, and therapeutic targets at single-cell resolution.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC=\"FIGDIR/small/792200v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@18fed35org.highwire.dtl.DTLVardef@1e68b7org.highwire.dtl.DTLVardef@6cfbc8org.highwire.dtl.DTLVardef@1061a26_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIA comprehensive single-cell resolution transcriptional landscape of mouse neutrophil maturation and fate decision under steady-state and bacterial infection conditions.\nC_LIO_LIThe pathogen clearance machinery in neutrophils is continuously and gradually built during neutrophil differentiation, maturation, and aging, driven by both known and uncharacterized transcription factors.\nC_LIO_LIThe three mature neutrophil subsets in peripheral blood, including a novel ISG-expressing subset, are derived from distinct bone marrow neutrophil precursors.\nC_LIO_LIBacterial infection reprograms the genetic architecture of neutrophil populations, alters dynamic transition between each subpopulation, and primes neutrophils for augmented functionality without affecting overall neutrophil heterogeneity.\nC_LIO_LIBacterial infection-induced emergency granulopoiesis is mediated by augmented proliferation of early stage neutrophil progenitors and accelerated post-mitotic maturation.\nC_LI

immunology↗

bioRxiv2019

Computational redesign of PETase for plastic biodegradation by GRAPE strategy

The excessive use of plastics has been accompanied by severe ecologically damaging effects. The recent discovery of a PETase from Ideonella sakaiensis that decomposes poly(ethylene terephthalate) (PET) under mild conditions provides an attractive avenue for the biodegradation of plastics. However, the inherent instability of the enzyme limits its practical utilization. Here, we devised a novel computational strategy (greedy accumulated strategy for protein engineering, GRAPE). A systematic clustering analysis combined with greedy accumulation of beneficial mutations in a computationally derived library enabled the design of a variant, DuraPETase, which exhibits an apparent melting temperature that is drastically elevated by 31 {degrees}C and strikingly enhanced degradation performance toward semicrystalline PET films (23%) at mild temperatures (over two orders of magnitude improvement). The mechanism underlying the robust promotion of enzyme performance has been demonstrated via a crystal structure and molecular dynamics simulations. This work shows the capabilities of computational enzyme design to circumvent antagonistic epistatic effects and provides a valuable tool for further understanding and advancing polyester hydrolysis in the natural environment.

synthetic biology↗

bioRxiv2019

Electroacupuncture at Governor Vessel improves neurobehavioral function via reduction of complexin1

Electroacupuncture at Governor Vessel (GV), as a traditional chinese medicine, has been proved that it can reduce scar and promote axon regeneration. However, the underlying mechanism remains unclear. Herein, complexin1 (CPLX1), as a candidate protein, was found using protein chip. Therefore, using a CRISPR/Cas9 knockout approach, we deleted CPLX1 specifically in the SD rats to assess the role of CPLX1 in GV treatment. Additionally, eIF5A1 stimulate the translation of CPLX1 with PPG sequence, we attempt to uncover whether eIF5A1 play a role in the GV treatment. In fact, GV can reduce scar and promote axon regeneration after SCC. CPLX1-/+ SCC rats demonstrated that decreased CPLX1 improved the microenvironment of injured area via reducing the components of fibrotic scar and further enhanced the synaptic plasticity, which benefit the regeneration of axons. And eIF5A1 could regulate the expression of CPLX1 in the process of GV treatment. Therefore, GV contributes to axon regeneration and synapse plasticity via eIF5A1 regulating CPLX1 following SCC, providing a convincible mechanism for improving the therapeutic efficacy of GV for SCC.

neuroscience↗

bioRxiv2019

Pathway engineering in yeast for synthesizing the complex polyketide bikaverin

Fungal polyketides display remarkable structural diversity and bioactivity, and therefore the biosynthesis and engineering of this large class of molecules is therapeutically significant. Here, we successfully recoded, constructed and characterized the biosynthetic pathway of the formation of bikaverin, a tetracyclic polyketide with antibiotic, antifungal and anticancer properties, in S. cerevisiae. We used a green fluorescent protein (GFP) tagging strategy to identify the low expression of Bik1 (polyketide synthase) as the bottleneck step in the pathway, and a promoter exchange strategy to increase expression of Bik1 and bikaverin yield. To further increase product yield, we used an enzyme-fusion strategy to couple the monooxygenase (Bik2) and methyltransferase (Bik3) to efficiently channel intermediates between modifying enzymes, leading to a dramatic improvement of Bikaverin yield of nearly 60-fold. This study demonstrates that the biosynthesis of complex polyketides biosynthesis can be established and efficiently engineered in S. cerevisiae, highlighting the great potential for natural product synthesis and large-scale fermentation in yeast.

synthetic biology↗

bioRxiv2019

Associations of adverse lifetime experiences with brain structure in 7003 UK Biobank participants

BackgroundExperiences of chronic stress and trauma are major risk factors for psychiatric illness. Evidence suggests that adversity-related changes in brain structure and function accelerate this vulnerability. It is yet to be determined whether neuroendocrine effects on the brain are a result of the interference with neural development during sensitive periods or a consequence of cumulative lifetime adversity. To address this question, the present study investigated the associations between brain structure and self-reported data of childhood and adult adversity using machine learning techniques and structural equation models (SEM).\n\nMethodsThe UK Biobank resource was used to access Imaging Derived Phenotypes (IDPs) of grey matter and white matter tract integrity of 7003 participants, together with selected childhood and adult adversity data. Latent measures of adversity and imaging phenotypes were estimated to evaluate their associations using SEM.\n\nResultsWe demonstrated that increased incidence of childhood adversity events may be associated with smaller grey matter in frontal, insular, subcallosal and cerebellar regions of the brain. There were no significant associations between brain phenotypes and negative experiences during adulthood.\n\nConclusionsUsing a large population cohort dataset, this study contributes to the suggestion that childhood adversity may determine grey matter reductions in brain regions, which are putatively sensitive to the neurotoxic effects of chronic stress. Furthermore, it provides novel evidence to support the \"sensitive periods\" model though which adversity affects the brain.

neuroscience↗

bioRxiv2019

KDDANet-a novel computational framework for systematic uncovering hidden gene interactions underlying known drug-disease associations

Many of genes mediating Known Drug-Disease Association (KDDA) are escaped from experimental detection. Identifying of these genes (hidden genes) is of great significance for understanding disease pathogenesis and guiding drug repurposing. Here, we presented a novel computational tool, called KDDANet, for systematic and accurate uncovering the hidden genes mediating KDDA from the perspective of genome-wide functional gene interaction network. KDDANet demonstrated the competitive performances in both sensitivity and specificity of identifying genes in mediating KDDA in comparison to the existing state-of-the-art methods. Case studies on Alzheimers disease (AD) and obesity uncovered the mechanistic relevance of KDDANet predictions. Furthermore, when applied with multiple types of cancer-omics datasets, KDDANet not only recapitulated known genes mediating KDDAs related to cancer, but also revealed novel candidates that offer new biological insights. Importantly, KDDANet can be used to discover the shared genes mediating multiple KDDAs. KDDANet can be accessed at http://www.kddanet.cn and the code can be freely downloaded at https://github.com/huayu1111/KDDANet.

bioinformatics↗

bioRxiv2019

Genomic dissection of 43 serum urate-associated loci provides multiple insights into molecular mechanisms of urate control.

Serum urate is the end-product of purine metabolism. Elevated serum urate is causal of gout and a predictor of renal disease, cardiovascular disease and other metabolic conditions. Genome-wide association studies (GWAS) have reported dozens of loci associated with serum urate control, however there has been little progress in understanding the molecular basis of the associated loci. Here we employed trans-ancestral meta-analysis using data from European and East Asian populations to identify ten new loci for serum urate levels. Genome-wide colocalization with cis-expression quantitative trait loci (eQTL) identified a further five new loci. By cis- and trans-eQTL colocalization analysis we identified 24 and 20 genes respectively where the causal eQTL variant has a high likelihood that it is shared with the serum urate-associated locus. One new locus identified was SLC22A9 that encodes organic anion transporter 7 (OAT7). We demonstrate that OAT7 is a very weak urate-butyrate exchanger. Newly implicated genes identified in the eQTL analysis include those encoding proteins that make up the dystrophin complex, a scaffold for signaling proteins and transporters at the cell membrane; MLXIP that, with the previously identified MLXIPL, is a transcription factor that may regulate serum urate via the pentose-phosphate pathway; and MRPS7 and IDH2 that encode proteins necessary for mitochondrial function. Trans-ancestral functional fine-mapping identified six loci (RREB1, INHBC, HLF, UBE2Q2, SFMBT1, HNF4G) with colocalized eQTL that contained putative causal SNPs (posterior probability of causality > 0.8). This systematic analysis of serum urate GWAS loci has identified candidate causal genes at 19 loci and a network of previously unidentified genes likely involved in control of serum urate levels, further illuminating the molecular mechanisms of urate control.\n\nAuthor SummaryHigh serum urate is a prerequisite for gout and a risk factor for metabolic disease. Previous GWAS have identified numerous loci that are associated with serum urate control, however, only a small handful of these loci have known molecular consequences. The majority of loci are within the non-coding regions of the genome and therefore it is difficult to ascertain how these variants might influence serum urate levels without tangible links to gene expression and / or protein function. We have applied a novel bioinformatic pipeline where we combined population-specific GWAS data with gene expression and genome connectivity information to identify putative causal genes for serum urate associated loci. Overall, we identified 15 novel serum urate loci and show that these loci along with previously identified loci are linked to the expression of 44 genes. We show that some of the variants within these loci have strong predicted regulatory function which can be further tested in functional analyses. This study expands on previous GWAS by identifying further loci implicated in serum urate control and new causal mechanisms supported by gene expression changes.

genetics↗

bioRxiv2019

Considering founding and variable genomes is critical in studying polyploid evolution

A wide range of differences between the subgenomes, termed as subgenome asymmetry or SA, has been reported in various polyploids and different species seem to have different responses to polyploidization. We compared subgenome differences in gene ratio and relative diversity between artificial and natural genotypes of several allopolyploid species. Surprisingly, consistent differences in neither gene ratio nor relative diversity between the subgenomes were detected between these two types of polyploid genotypes although they differ in times exposed to evolutional selection. As expected, the estimated ratio of retained genes between a subgenome and its diploid donor was invariably higher for the artificial allopolyploid genotypes due likely to the presence of variable genome components (VGC). Clearly, the presence of VGC means that exaggerated differences between a donor and a subgenome in a polyploid are inevitable when random genotypes were used to represent species of either a polyploid or its donors. SA was also detected in genotypes before the completion of the polyploidization events as well as in those which were not formed via polyploidization. Considering that significant changes during and following polyploidization have been detected in previous studies, our results suggest that the influence of VGC needs to be considered in evaluating SA and that diploid donors may define changes in polyploid evolution.

evolutionary biology↗

bioRxiv2019

Geomagnetic field intensity may be a cue for the regulation of insect migration

Geomagnetic field (GMF) intensity can be used by some animals to determine their direction and position during migration. However, its role, if any, in mediating other migration-related phenotypes remains largely unknown. Here, we simulated variation in GMF intensity between two locations along the migration route of a nocturnal insect migrant, the brown planthopper Nilaparvata lugens, that varied by [~]5 T (GMF50T vs. GMF45T) in field intensity. After one generation of exposure, we tested for changes in key morphological, behavioural and physiological traits related to migratory performance including wing dimorphism, flight capacity and positive phototaxis. Our results showed that all three morphological and behavioural phenotypes responded to a small difference in magnetic field intensity between the simulated northern vs. southern locations in ways expected along the migratory route. Consistent magnetic responses in the expression of the phototaxis-related Drosophila-like cryptochrome 1 (Cry1) gene and levels of two primary energy substrates used during flight, triglyceride and trehalose, were also found. Our findings indicate GMF intensity can be a cue that regulates the expression of phenotypes critical for insect migration and highlight the unique role of magnetoreception as a trait that can help migratory insects express potentially beneficial phenotypes in geographically variable environments.

animal behavior and cognition↗

bioRxiv2019

Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1

The molecular and genetic mechanisms by which different single nucleotide variant (SNV) alleles in specific genes, or at the same genetic locus, bring about distinct disease phenotypes often remain unclear. Allelic truncating mutations of fibrillin-1(FBN1) cause either classical Marfan syndrome (MFS) or a more severe phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). A total of three Marfan syndrome/Marfanoid patients (2 singletons and 1 parent-offspring trio) were recruited. Targeted next-generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, patient clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. We investigated a small cohort, consisting of two classical MFS and one MPLS patient from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. We provide evidence that most nonsense and frameshift mutations lead to FBN1 null alleles due to mutant mRNA transcript degradation. In contrast, the more severe disease phenotype, MPLS, is caused by mutant mRNAs that are predicted to escape the nonsense mediated decay (NMD) surveillance pathway, making a mutant protein that exerts a dominant negative interference effect to FBN1 thus generating a gain-of-function (GoF) rather than a loss-of-function (LoF) allele as in MFS. Overall, we provide direct evidence that a dominant negative interaction of FBN1 potentially explains the distinct clinical phenotype in MPLS patients through genetic and functional analysis of the first Chinese patient with MPLS. Moreover, our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS patients.

genetics↗