Biology subjects

Wan, S.

Publications and source records attributed to Wan, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

RanBALL: An Ensemble Random Projection Model for Identifying Subtypes of B-cell Acute Lymphoblastic Leukemia

As the most common pediatric malignancy, B-cell acute lymphoblastic leukemia (B-ALL) has multiple distinct subtypes characterized by recurrent and sporadic somatic and germline genetic alterations. Identifying B-ALL subtypes can facilitate risk stratification and enable tailored therapeutic design. Existing methods for B-ALL subtyping primarily depend on immunophenotyping, cytogenetic tests and genomic profiling, which would be costly, complicated, and laborious. To overcome these challenges, we present RanBALL (an ensemble Random projection-based model for identifying B-ALL subtypes), an accurate and cost-effective model for B-ALL subtype identification. By leveraging random projection (RP) and ensemble learning, RanBALL can preserve patient-to-patient distances after dimension reduction and yield robustly accurate classification performance for B-ALL subtyping. Benchmarking results based on >1700 B-ALL patients demonstrated that RanBALL achieved remarkable performance (accuracy: 0.93, F1-score: 0.93, and Matthews correlation coefficient: 0.93), significantly outperforming state-of-the-art methods like ALLSorts in terms of all performance metrics. In addition, RanBALL performs better than tSNE in terms of visualizing B-ALL subtype information. We believe RanBALL will facilitate the discovery of B-ALL subtype-specific marker genes and therapeutic targets to have consequential positive impacts on downstream risk stratification and tailored treatment design. To extend its applicability and impacts, a Python-based RanBALL package is available at https://github.com/wan-mlab/RanBALL.

bioinformatics↗

bioRxiv2024

The cornerstone of early diagnosis and immunotherapy of prostate cancer:screening characteristic genes

BackgroundProstate cancer (PCA) has become a common malignant tumor globally, posing a substantial risk to the health of middle-aged and elderly men. However, there is still a lack of effective strategies for early detection and treatment of prostate cancer. The introduction of gene therapy in recent years has shown promise as a potential approach for cancer diagnosis and treatment. Methodology & Theoretical OrientationThe training set data GSE45016, GSE46602, and GSE69223 from the Gene Expression Omnibus (GEO) dataset, along with validation training set data GSE17951, were utilized. Differentially expressed genes (DEGs) between normal individuals and tumor patients were identified by combining the training set data. Subsequent analyses including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were conducted on the DEGs. WGCNA analysis was then performed on the gene expression matrix to identify module genes highly correlated with PCA, followed by the application of the LASSO algorithm to obtain PCA candidate genes. The candidate genes were validated using the area under the receiver operating characteristic (ROC) curve (AUC) to determine key feature genes. Finally, the relationship between key characteristic genes and immune cells was explored. FindingsA total of 54 DEGs were identified, with 26 down-regulated genes and 28 up-regulated genes. The GO function analysis revealed enrichment in processes such as establishment of protein localization to membrane and protein targeting to membrane. KEGG analysis showed enrichment in pathways like eutrophil degranulation, neutrophil activation involved in immune response, and regulation of cell morphogenesis. GSEA analysis highlighted enrichment in pathways like CTRL_VS_ACT_IL4 AND ANTI_IL12_12H_CD4_TCELL_DN. Through WGCNA and LASSO regression analysis, key characteristic genes MARCKSL1, TMTC4, and TTLL12 were identified, with AUC values greater than 0.8 in both the training and validation sets, and were found to be closely associated with immune cell infiltration. Conclusion & SignificanceMARCKSL1, TMTC4, and TTLL12 emerge as crucial genes in the process of PCA, showing significant relevance to immune cell infiltration.this study offers valuable clinical insights into the diagnosis and treatment of prostate cancer through the identification of specific genes associated with the disease.

genomics↗

bioRxiv2024

SAMP: Identifying Antimicrobial Peptides by an Ensemble Learning Model Based on Proportionalized Split Amino Acid Composition

AbstractIt is projected that 10 million deaths could be attributed to drug-resistant bacteria infections in 2050. To address this concern, identifying new-generation antibiotics is an effective way. Antimicrobial peptides (AMPs), a class of innate immune effectors, have received significant attention for their capacity to eliminate drug-resistant pathogens, including viruses, bacteria, and fungi. Recent years have witnessed widespread applications of computational methods especially machine learning (ML) and deep learning (DL) for discovering AMPs. However, existing methods only use features including compositional, physiochemical, and structural properties of peptides, which cannot fully capture sequence information from AMPs. Here, we present SAMP, an ensemble random projection (RP) based computational model that leverages a new type of features called Proportionalized Split Amino Acid Composition (PSAAC) in addition to conventional sequence-based features for AMP prediction. With this new feature set, SAMP captures the residue patterns like sorting signals at around both the N-terminus and the C-terminus, while also retaining the sequence order information from the middle peptide fragments. Benchmarking tests on different balanced and imbalanced datasets demonstrate that SAMP consistently outperforms existing state-of-the-art methods, such as iAMPpred and AMPScanner V2, in terms of accuracy, MCC, G-measure and F1-score. In addition, by leveraging an ensemble RP architecture, SAMP is scalable to processing large-scale AMP identification with further performance improvement, compared to those models without RP. To facilitate the use of SAMP, we have developed a Python package freely available at https://github.com/wan-mlab/SAMP.

bioinformatics↗

bioRxiv2024

Seaweed Amino Acid and L-Amino Acid Improve Coriander Growth

This study investigates the impact of Seaweed amino acid (SG) and L-amino acid (LG) treatments on the growth and root development of coriander plants compared to a control group (CG). The results from Figure 1 illustrate a significant increase in biomass and foliage density for the SG and LG groups, suggesting an enhanced nutritional uptake resulting from these amino acid treatments. Both SG and LG treatments produced more vigorous growth and higher plant height compared to the CG, which received only water. Additionally, a closer inspection of coriander root systems in Figure 2 reveals an improvement in root biomass and architecture, indicating that both SG and LG applications contribute positively to root development, potentially enhancing plant resilience and yield. While both treatments showed comparable effects on root morphology, further research is required to determine if one has superior long-term benefits over the other. The findings point towards the efficacy of using amino acid treatments as bio-stimulants in agricultural practices to improve crop yield, especially in challenging growth conditions such as those found in Guangzhou, China. O_FIG O_LINKSMALLFIG WIDTH=185 HEIGHT=200 SRC="FIGDIR/small/585645v1_fig1.gif" ALT="Figure 1"> View larger version (144K): org.highwire.dtl.DTLVardef@84ada8org.highwire.dtl.DTLVardef@a51dfeorg.highwire.dtl.DTLVardef@544772org.highwire.dtl.DTLVardef@11e9adf_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:C_FLOATNO Comparative Analysis of Coriander Growth Response to Root Applications of Seaweed Amino Acid (SG) and L-amino Acid (LG). Top Left (SG): Coriander plants treated with seaweed amino acid at 100 ppm, showing dense foliage. Top Right (LG): Coriander plants treated with L-amino acid at 100 ppm, exhibiting similar vegetative growth. Bottom Left (CG): Control coriander plants irrigated only with water, with noticeably less growth. Bottom Right: Comparative height analysis of harvested coriander plants, demonstrating the impact of SG and LG treatments versus the control group. C_FIG O_FIG O_LINKSMALLFIG WIDTH=120 HEIGHT=200 SRC="FIGDIR/small/585645v1_fig2.gif" ALT="Figure 2"> View larger version (92K): org.highwire.dtl.DTLVardef@49b047org.highwire.dtl.DTLVardef@1d42543org.highwire.dtl.DTLVardef@da7ec1org.highwire.dtl.DTLVardef@b7c5db_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 2.C_FLOATNO Differential Impact of Seaweed Amino Acid (SG) and L-amino Acid (LG) Treatments on Coriander Root Morphology. The image presents a comparative view of coriander root systems after treatment with Seaweed amino acids (SG) and L-amino acids (LG) against a control group (CG). The control group roots (top row) display a baseline development, having been irrigated solely with water. The SG group roots (middle row) exhibit enhanced development, indicative of the positive influence of Seaweed amino acid treatment. In contrast, the LG group roots (bottom row) show a comparable advancement in root structure to the SG group, suggesting both amino acid treatments contribute to improved root architecture and possibly, plant resilience at harvest. C_FIG

plant biology↗

bioRxiv2024

Cryo-EM structures of human cone visual pigments

Trichromatic color vision in humans constitutes a pivotal evolutionary adaptation, endowing individuals with the capacity to discern and discriminate a diverse spectrum of colors. This unique visual capability confers a selective advantage crucial for successful adaptation, survival, and reproductive success in the natural environment. Color vision in humans is facilitated by the red, green, and blue cone visual pigments within cone photoreceptor cells. These pigments consist of a G-protein-coupled receptor opsin apoprotein and a chromophore covalently linked to opsins. Despite the elucidated structure of rhodopsin, the structures of cone visual pigments have yet to be determined. Here, we present the cryo-EM structures of three human cone visual pigments in complex with G proteins. Our structural analysis reveals detailed interactions between cone opsins, all-trans-retinal, and G proteins, indicating their active state. We also provide a concise summary and analysis of mutations in human cone opsins, elucidating potential relationships between residue substitutions and spectral tuning. Notably, S1162.67Y, A2335.52S, Y2776.44F were found to induce a blue shift in the absorption spectrum of the red-pigment, while the substitutions W2816.48Y and K3127.43A resulted in the absence of the absorption spectrum. The structural elucidation of human cone visual pigments significantly contributes to our understanding of how distinct types of cone cells perceive light across varying wavelengths. Furthermore, it provides a deeper insight into the functioning of the human trichromatic vision system, probing the mechanisms enabling humans to perceive a broad spectrum of colors.

biophysics↗

bioRxiv2023

PVN microglia via P2Y12 transmit hemodynamic signal to promote sympathetic excitation in hypertension

Hypertension is usually accompanied with an elevated sympathetic tonicity, but how sympathetic hyperactivity is triggered is not fully understood. Recent advances reveal that microglia-centered neuroinflammation contributes to sympathetic excitation in hypertension. In this study, we performed a temporospatial analysis of microglia at both morphological and transcriptomic levels, and found that microglia in the hypothalamic paraventricular nucleus (PVN) were early responders to hypertensive challenges. PVN is the central hub for maintaining cardiovascular function via regulation of fluid balance and sympathetic outflow. Comprehensive vasculature analyses unveiled that PVN was characterized by high capillary density, thin vessel diameter, and complex vascular topology among brain regions. As such, PVN is susceptible to the penetration of ATP released from the vasculature in response to hemodynamic disturbance after blood pressure increase. ATP ligation to microglial P2Y12 receptor is responsible for the microglial accumulation and activation in the PVN. Furthermore, either pharmacological blockade or genetic ablation of microglial P2Y12 could substantially restrain blood pressure increase under hypertensive challenge. Together, these findings disclose that a unique vasculature pattern results in the vulnerability of PVN pre-sympathetic neurons to hypertension-associated insults, which is mediated by microglia.

neuroscience↗

bioRxiv2023

scTIE: data integration and inference of gene regulation using single-cell temporal multimodal data

Single-cell technologies offer unprecedented opportunities to dissect gene regulatory mecha-nisms in context-specific ways. Although there are computational methods for extracting gene regulatory relationships from scRNA-seq and scATAC-seq data, the data integration problem, essential for accurate cell type identification, has been mostly treated as a standalone challenge. Here we present scTIE, a unified method that integrates temporal multimodal data and infers regulatory relationships predictive of cellular state changes. scTIE uses an autoencoder to embed cells from all time points into a common space using iterative optimal transport, followed by extracting interpretable information to predict cell trajectories. Using a variety of synthetic and real temporal multimodal datasets, we demonstrate scTIE achieves effective data integration while preserving more biological signals than existing methods, particularly in the presence of batch effects and noise. Furthermore, on the exemplar multiome dataset we generated from differentiating mouse embryonic stem cells over time, we demonstrate scTIE captures regulatory elements highly predictive of cell transition probabilities, providing new potentials to understand the regulatory landscape driving developmental processes.

bioinformatics↗

bioRxiv2022

High air humidity dampens salicylic acid pathway and plant resistance via targeting of NPR1

The occurrence of plant disease is determined by interactions among host, pathogen and climate conditions. Air humidity has long been recognized to profoundly influence diseases in the phyllosphere and high air humidity (e.g., after rain falls) is known as a prerequisite for numerous disease outbreaks in the field1-3. However, the molecular basis of how high humidity interferes with plant resistance mechanisms to favor disease remained elusive. Here we show that high humidity is associated with an "immune-compromised" status of plants, revealed by lower expression of defense genes during bacterial infection of Arabidopsis plants. Examination of humiditys effect on individual immune pathways showed that the accumulation and signaling of salicylic acid (SA), an essential hormone conferring plant resistance against infectious microbes4,5, are significantly inhibited under high humidity. Surprisingly, NPR1 protein, an SA receptor and central transcriptional co-activator of SA-responsive genes6-9, accumulated to a significantly higher level in the nucleus under high humidity. Further investigation indicated a decreased binding affinity of NPR1 protein to the target gene promoter, suggestive of an "inactive" nature of NPR1, under high humidity and an impaired ubiquitination and degradation of NPR1 protein, likely due to down-regulation of Cullin 3-mediated cellular ubiquitination pathway and 26S proteasome pathway under high humidity. Our study uncovers disruption of NPR1 protein turnover as a major mechanism, by which high humidity dampens plant immune strength against pathogens, and provides new insights into the long-observed air humidity influence on diseases in nature.

plant biology↗

bioRxiv2022

A potent SARS-CoV-2 neutralizing antibody recognizing a conserved epitope with broad mutant variant and SARS-CoV activity.

COVID-19 is the deadliest respiratory virus pandemic since 1918 and the latest of several coronavirus epidemics and pandemics in recent years. Despite the unprecedented response by both the government and private sectors to develop vaccines and therapies, the evolution of SARS-CoV-2 variants resistant to these interventions reveals a crucial need for therapeutics that maintain their efficacy against current and future mutant variants. Here we describe a SARS-CoV-2 neutralizing antibody, ABP-310, with potent activity against all variants tested including the Omicron variant. ABP-310 also displays potent neutralizing activity against SARS-CoV, highlighting the conserved nature of the ABP-310 epitope. By targeting a conserved epitope, we believe that ABP-310 has therapeutic promise not only against the current SARS-CoV-2 variants but would be expected to maintain efficacy against future variants and possibly even novel coronaviruses.

microbiology↗

bioRxiv2021

YAP/TAZ Maintain the Proliferative Capacity and Structural Organization of Radial Glial Cells During Brain Development

The Hippo pathway regulates the development and homeostasis of many tissues and in many species. It controls the activity of two paralogous transcriptional coactivators, YAP and TAZ (YAP/TAZ). Although previous studies have established that aberrant YAP/TAZ activation is detrimental to mammalian brain development, whether and how endogenous levels of YAP/TAZ activity regulate brain development remain unclear. Here, we show that during mammalian cortical development, YAP/TAZ are specifically expressed in apical neural progenitor cells known as radial glial cells (RGCs). The subcellular localization of YAP/TAZ undergoes dynamic changes as corticogenesis proceeds. YAP/TAZ are required for maintaining the proliferative potential and structural organization of RGCs, and their ablation during cortical development reduces the numbers of cortical projection neurons and causes the loss of ependymal cells, resulting in hydrocephaly. Transcriptomic analysis using sorted RGCs reveals gene expression changes in YAP/TAZ-depleted cells that correlate with mutant phenotypes. Thus, our study has uncovered essential functions of YAP/TAZ during mammalian brain development and revealed the transcriptional mechanism of their action.

developmental biology↗

bioRxiv2021

scJoint: transfer learning for data integration of single-cell RNA-seq and ATAC-seq

Single-cell multi-omics data continues to grow at an unprecedented pace, and effectively integrating different modalities holds the promise for better characterization of cell identities. Although a number of methods have demonstrated promising results in integrating multiple modalities from the same tissue, the complexity and scale of data compositions typically present in cell atlases still pose a significant challenge for existing methods. Here we present scJoint, a transfer learning method to integrate atlas-scale, heterogeneous collections of scRNA-seq and scATAC-seq data. scJoint leverages information from annotated scRNA-seq data in a semi-supervised framework and uses a neural network to simultaneously train labeled and unlabeled data, enabling label transfer and joint visualization in an integrative framework. Using multiple atlas data and a biologically varying multi-modal data, we demonstrate scJoint is computationally efficient and consistently achieves significantly higher cell type label accuracy than existing methods while providing meaningful joint visualizations. This suggests scJoint is effective in overcoming the heterogeneity in different modalities towards a more comprehensive understanding of cellular phenotypes.

bioinformatics↗

bioRxiv2020

Cloning and Functional characterization of seed-specific LEC1A promoter from peanut (Arachis hypogaea L.)

LEAFY COTYLEDON1 (LEC1) is a HAP3 subunit of CCAAT-binding transcription factor, which controls several aspects of embryo and postembryo development, including embryo morphogenesis, storage reserve accumulation and skotomorphogenesis. Herein, using the method of chromosomal walking, a 2707bp upstream sequence from the ATG initiation codon site of AhLEC1A which is a homolog of Arabidopsis LEC1 was isolated in peanut. Its transcriptional start site confirmed by 5 RACE was located at 82 nt from 5 upstream of ATG. The bioinformatics analysis revealed that there existed many tissue-specific elements and light responsive motifs in its promoter. To identify the functional region of the AhLEC1A promoter, seven plant expression vectors expressing the GUS ({beta}-glucuronidase) gene, driven by 5 terminal series deleted fragments of AhLEC1A promoter, were constructed and transformed into Arabidopsis. Results of GUS histochemical staining showed that the regulatory region containing 82bp of 5 UTR and 2228bp promoter could facilitate GUS to express preferentially in the embryos at different development periods of Arabidopsis. Taken together, it was inferred that the expression of AhLEC1A during seed development of peanut might be controlled positively by several seed-specific regulatory elements, as well as negatively by some other regulatory elements inhibiting its expression in other organs. Moreover, the GUS expression pattern of transgenic seedlings in darkness and in light was relevant to the light-responsive elements scattered in AhLEC1A promoter segment, implying that these light-responsive elements harbored in the AhLEC1A promoter regulate skotomorphogenesis of peanut seeds, and AhLEC1A expression was inhibited after the germinated seedlings were transferred from darkness to light.

molecular biology↗

bioRxiv2020

Characterizing tissue composition through combined analysis of single-cell morphologies and transcriptional states

Advances in spatial transcriptomics technologies enable optical profiling of morphological and transcriptional modalities from the same cells within tissues. Here, we present multi-modal structured embedding (MUSE), an approach to deeply characterize tissue heterogeneity through analysis of combined image and transcriptional single-cell measurements. We demonstrate that MUSE can discover cellular subpopulations missed by either modality as well as compensate for modality-specific noise. MUSE identified biologically meaningful cellular subpopulations and stereotyped spatial patterning within heterogeneous mouse cortex brain tissues, profiled by seqFISH+ or STARmap technologies. MUSE provides a framework for combining multi-modal single-cell data to reveal deeper insights into the states, functions and organization of cells in complex biological tissues.

bioinformatics↗

bioRxiv2020

Ursolic acid improves the bacterial community mapping of the intestinal tract in liver fibrosis mice

Liver fibrosis often appears in chronic liver disease, with extracellular matrix (ECM) deposition as the main feature. Due to the presence of the liver-gut axis, the destruction of intestinal homeostasis is often accompanied by the development of liver fibrosis. The inconsistent ecological environment of different intestinal sites may lead to differences in the microbiota. The traditional Chinese medicine Ursolic acid (UA) has been proven to protect the liver from fibrosis. We investigated the changes in the microbiota of different parts of the intestine during liver fibrosis and the effect of UA on these changes based on high-throughput sequencing technology. Sequencing results suggest that the diversity and abundance of intestinal microbiota decline and the composition of the microbiota is disordered, the potentially beneficial Firmicutes bacteria are reduced, and the pathways for functional prediction are changed in the ilea and anal faeces of liver fibrosis mice compared with normal mice. However, in UA-treated liver fibrosis mice, these disorders improved. It is worth noting that the bacterial changes in the ilea and anal faeces are not consistent. In conclusion, in liver fibrosis, the microbiota of different parts of the intestines have different degrees of disorder, and UA can improve this disorder. This may be a potential mechanism for UA to achieve anti-fibrosis. This study provides theoretical guidance for the UA targeting of intestinal microbiota for the treatment of liver fibrosis.

microbiology↗

bioRxiv2019

Explaining the genetic causality for complex diseases via deep association kernel learning

The genetic effect explains the causality from genetic mutation to the development of complex diseases. Existing genome-wide association study (GWAS) approaches are always built under a linear assumption, restricting their generalization in dissecting complicated causality such as the recessive genetic effect. Therefore, a sophisticated and general GWAS model that can work with different types of genetic effects is highly desired. Here, we introduce a Deep Association Kernel learning (DAK) model to enable automatic causal genotype encoding for GWAS at pathway level. DAK can detect both common and rare variants with complicated genetic effects that existing approaches fail. When applied to real-world GWAS data, our approach discovered potential casual pathways that could be explained by alternative biological studies.

bioinformatics↗

bioRxiv2019

Blue sky’s the limit? Somatic embryogenesis as a means of propagating recalcitrant blue spruce (Picea pungens) cultivar Hoopsii

The triple-blue cultivar of blue spruce (Picea pungens Hoopsii) is notably recalcitrant towards the realm of traditional vegetative propagation methods. Its ability to naturally proliferate is limited by ovule and embryo abortion during the growing season, leading to low viable seed yield. In this study, we established a protocol using somatic embryogenesis (SE) as a means of propagating this popular ornamental cultivar. We collected cones from Hoopsii trees at seven different timepoints throughout the growing season (mid-June to late July in Ottawa (Plant Hardiness Zone 5A)). Female megagametophytes were harvested following each collection and immature zygotic embryos were plated onto induction media. Early somatic embryos began developing from the embryonic tissue (ET) three to five weeks following induction. The highest ET initiation frequency occurred from embryos collected June 20-July 10, suggesting that developmental stage of the embryo was a significant factor in SE induction. The conversion of mature somatic embryos into plantlets (emblings) was completed in eight-ten weeks at a rate of 92.8%. In this study, we demonstrate that in vitro somatic embryogenesis using our optimized protocol is a fast and prolific method for the mass propagation of Hoopsii blue spruce. This is the first report on the production of somatic Hoopsii emblings.

plant biology↗

bioRxiv2019

Transcriptional Differences of Peanut (Arachis hypogaea L.) Seeds in the Fresh-harvest, After-ripened and Just-germinated States: insights into regulatory networks of seed dormancy-release and germination

Seed dormancy and germination are the two important traits related to plant survival and reproduction, and crop yield. To understand their regulation mechanism, it is crucial to clarify which genes or which pathways participate in the regulation of these processes. However, little information is available during the procedure of seed dormancy and germination in peanut. In this study, the seeds of the variety Luhua No.14 with non-deep dormancy were selected and its transcriptional changes at three developmental stages: the fresh-harvest (FS), the after-ripened (DS) and the just-germinated seeds (GS), were investigated by comparative transcriptomics analysis. The results showed that genes with increased transcription in DS vs FS comparison were overrepresented for oxidative phosphorylation, glycolysis pathway and tricarboxylic acid cycle (TCA), suggesting that after a period of drying storage, the intermediates stored in dry seeds were rapidly mobilized by glycolysis, TCA cycle, glyoxylate cycle, etc.; the electron transport chain accompanying with respiration has been reactivated to provide ATP for mobilization of other reserves and seed germination. In GS vs DS pairwise, dozens of the up-regulated genes were related to plant hormone biosynthesis and signal transduction, including the majority of components in auxin signal pathway, and brassinosteroid biosynthesis and signal transduction, and some GA and ABA signal transduction genes. During seeds germination, the expression of some EXPANSIN and XYLOGLUCAN ENDOTRANSGLYCOSYLASE was also significantly enhanced. To investigate the effect of different hormone during the procedure of seed germination, the contents and the differential distribution of ABA, GA, BR and IAA in cotyledon, hypocotyl and radicle, and plumule of three seed sections at different developmental stages were also detected. Combining with previous data in other species, a model of regulatory network related to peanut seed germination was developed. This model will helpful to gain further understanding of the mechanisms controlling seed dormancy and germination.

plant biology↗

bioRxiv2018

A novel nonsense mutation c.424G>T (p. G142X) in the first exon of XLas leading to osteopetrosis

GNAS is one of the most complex gene loci in the human genome and encodes multiple gene products. XLas, the extra-large isoform of alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gas), is paternally inherited. Although XLas can mimic the action of Gas, its significance remains largely unknown in humans. Here we report a patient presented with increased bone mass, hypophosphatemia, and elevated parathyroid hormone levels. His serum calcium was in the lower limit of normal range. DEXA scan revealed progressive increase in the bone density of this patient. Whole exome sequencing of this subject found a novel nonsense mutation c.424G>T (p. G142X) in the first exon of XLas, which was inherited from his father and transmitted to his daughter. This mutation was predicted to exclusively influence the expression of XLas, while may have no significant effects on other gene products of this locus. SaOS2 cells transfected with mutant XLas failed to generate cAMP under parathyroid hormone stimulation, indicating skeletal resistance to this hormone. This subject showed higher circulating SOST, DKK1 and OPG levels, while lower RANKL levels and RANKL/OPG ratio, leading to reduced bone resorption. It is speculated that this patient may belong to a very rare type of pseudohypoparathyroidism with selective skeletal resistance but normal renal tubular response to parathyroid hormone. Our findings indicate that XLas plays a critical role in bone metabolism and GNAS locus should be considered as a candidate gene for high bone mass.\n\nAuthor summaryGNAS has been regarded as one of the most complex gene loci and encodes multiple transcripts, including Gs, XLs, NESP55 and A/B transcripts. These isoforms share the same 2-13 exons with alternative first exons. Previously reported mutations often disrupt multiple protein-coding transcripts in addition to that encoding Gs, making it difficult to distinguish the contributions of each transcript to disease phenotypes. Here we first report a novel nonsense mutation c.424G>T (p. G142X) in the first exon of XLas in a subject presenting with high bone mass, unclosed cranial suture, and persistent hypophosphatemia, and elevated parathyroid hormone (PTH) levels. This is the first report of a mutation located in the first exon of XLas in humans, which was predicted to exclusively influence the expression of XLas, while may have no significant effects on other gene products of this locus. SaOS2 cells transfected with mutant XLas failed to generate cAMP under PTH stimulation, indicating skeletal resistance to this hormone. Our study suggests that XLas has an important physiological role in humans, and is involved in skeletal PTH/cAMP pathway. Our findings also indicate GNAS locus should be considered as a candidate gene for high bone mass.\n\nFundingThe National Natural Science Foundation of China.\n\nDeclaration of InterestsThe authors declare no competing interests.

genetics↗