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PubMed2001

Metabolism 2000: the emperor needs new clothes.

Metabolism is one of the corner stones of nutritional science. As biology enters the post-genomic era and with functional genomics beginning to takeoff, we anticipate that the study of metabolism will play an increasingly important role in helping to link advances made via the reductionist paradigm, that has been so successful in molecular and cellular biology, with those emerging from observational studies in animals and human subjects. A reconstructive metabolically-focused approach offers a timely paradigm for enhancing the elegance of nutritional science. Here we give particular attention to the use of tracers as phenotyping tools and discuss the application of our metaprobe concepts with respect to some novel features of metabolism, including 'underground metabolism', 'metabolic hijacking', 'catalytic promiscuity' and 'moonlighting proteins'. The opportunities for enhancing the study of metabolism by new and emerging technologies, and the importance of the interdisciplinary research enterprise are also touched upon. We conclude that: (1) the metaprobe concepts and approach, discussed herein, potentially yield a quantitative physiological (metabolic) phenotype against which to elaborate partial or focused genotypes; (2) physiological (metabolic) phenotypes which have a whole-body or kinetically-discernible inter-organ tissue-directed metabolic signature are an ideal target for this directed tracer-based definition of the 'functional' genotype; (3) metabolism, probed with tracer tool kits suitable for measuring rates of turnover, change and conversion, becomes in the current sociology of the 'Net', like AOL, Yahoo. Alta Vista, Lycos or Ask Jeeves, the portal for an exploration of the metabolic characteristics of the 'Genomics Internet'.

Aging↗

PubMed2006

RNA interference of the salivary gland nitrophorin 2 in the triatomine bug Rhodnius prolixus (Hemiptera: Reduviidae) by dsRNA ingestion or injection.

Mass sequencing of cDNA libraries from salivary glands of triatomines has resulted in the identification of many novel genes of unknown function. The aim of the present work was to develop a functional RNA interference (RNAi) technique for Rhodnius prolixus, which could be widely used for functional genomics studies in triatomine bugs. To this end, we investigated whether double-stranded RNA (dsRNA) can inhibit gene expression of R. prolixus salivary nitrophorin 2 (NP2) and what impact this might have on anticoagulant and apyrase activity in the saliva. dsRNA was introduced by two injections or by ingestion. RT-PCR of the salivary glands showed that injections of 15 microg of NP2 dsRNA in fourth-instar nymphs reduced gene expression by 75+/-14% and that feeding 1 microg/microL of NP2 dsRNA into second-instar nymphs (approx. 13 microg in total) reduced gene expression by 42+/-10%. Phenotype analysis showed that saliva of normal bugs prolonged plasma coagulation by about four-fold when compared to saliva of knockdown bugs. These results and the light color of the salivary gland content from some insects are consistent with the knockdown findings. The findings suggest that RNAi will prove a highly valuable functional genomics technique in triatomine bugs. The finding that feeding dsRNA can induce knockdown is novel for insects.

Animals↗

PubMed2005

Random walk models for bayesian clustering of gene expression profiles.

The analysis of gene expression temporal profiles is a topic of increasing interest in functional genomics. Model-based clustering methods are particularly interesting because they are able to capture the dynamic nature of these data and to identify the optimal number of clusters. We have defined a new Bayesian method that allows us to cope with some important issues that remain unsolved in the currently available approaches: the presence of time dislocations in gene expression, the non-stationarity of the processes generating the data, and the presence of data collected on an irregular temporal grid. Our method, which is based on random walk models, requires only mild a priori assumptions about the nature of the processes generating the data and explicitly models inter-gene variability within each cluster. It has first been validated on simulated datasets and then employed for the analysis of a dataset relative to serum-stimulated fibroblasts. In all cases, the results have been promising, showing that the method can be helpful in functional genomics research.

Journal Article↗

PubMed2000

Systematic management and analysis of yeast gene expression data.

We report steps toward the systematic management, standardization, and analysis of functional genomics data. We developed the ExpressDB database for yeast RNA expression data and loaded it with approximately 17.5 million pieces of data reported by 11 studies with three different kinds of high-throughput RNA assays. A web-based tool supports queries across the data from these studies. We examined comparability of data by converting data from 9 studies (217 conditions) into mRNA relative abundance estimates (ERAs) and by clustering of conditions by ERAs. We report on generation of ERAs and condition clustering for non-microarray data (5 studies, 63 conditions) and describe initial attempts to generate microarray-based ERAs (4 studies, 154 conditions), which exhibit increased error, on our web site http://arep.med.harvard. edu/ExpressDB. We recommend standards for data reporting, suggest research into improving comparability of microarray data through quantifying and standardizing control condition RNA populations, and also suggest research into the calibration of different RNA assays. We introduce a model for a database that integrates different kinds of functional genomics data, Biomolecule Interaction, Growth and Expression Database (BIGED).

Computational Biology↗

PubMed2026

A stable transformation platform in pomegranate uncovers PgMYB10 as a key regulator of anthocyanin biosynthesis.

An efficient genetic transformation platform enables functional validation of PgMYB10, identifying it as a master regulator governing anthocyanin biosynthesis in pomegranate. Limited availability of stable genetic transformation systems restricts functional genomics research in pomegranate. Here, we established efficient in vitro regeneration and Agrobacterium tumefaciens-mediated transformation systems for 'Taishanhong' pomegranate using stem segment explants. Optimized medium combinations produced high-frequency regeneration: a 93.3% shoot-induction rate on MS medium with 1.5 mg/L 6-benzylaminopurine (BAP), 0.6 mg/L 1-naphthaleneacetic acid (NAA) and 30.0 mg/L adenine sulfate (ADS); a proliferation coefficient of 5.4 on MS medium supplemented with 0.8 mg/L BAP and 0.3 mg/L indole‑3‑butyric acid (IBA); effective shoot-strengthening on MS medium containing 1.2 mg/L BAP, 0.3 mg/L NAA and 0.2 mg/L gibberellic acid (GA₃); and a rooting rate of 95.3% on half-strength MS medium with 1.5 mg/L IBA and 0.5 mg/L NAA. For transformation, precultured explants were immersed with A. tumefaciens suspension (OD₆₀₀ = 0.8) containing 20.0 mg/L acetosyringone (AS) for 30 min. After four days of dark co-culture, sequential antibiotic screening with 30 mg/L kanamycin and bacteriostatic treatment with 400 mg/L timentin yielded a stable average transformation efficiency of 17.5% in 'Taishanhong' pomegranate. Subsequent functional analysis revealed that overexpression of PgMYB10 induced pigment accumulation in leaves and stems. In three independent transgenic lines, maximum anthocyanin content and PgMYB10 transcript levels were 5.4-fold and 27.2-fold higher than in wild-type plants, respectively. Six anthocyanin biosynthetic genes (PgCHS, PgCHI, PgF3H, PgDFR, PgANS, and PgUFGT) were markedly upregulated, demonstrating that PgMYB10 positively controls anthocyanin biosynthesis. This transformation system provides a reliable technical platform for functional genomic studies in pomegranate, and PgMYB10 represents as a promising candidate gene for molecular breeding aimed at improving fruit pigmentation.

Anthocyanins↗

PubMed2026

Novel Mycoparasitic Mechanisms and Colonization Patterns on Poplar Revealed by GFP Tagging of the Biocontrol Fungus Clonostachys reniana.

Clonostachys rosea has long been the primary model for studying mycoparasitism within its genus; however, the potential of other species remains largely unexplored. In this study, we established a PEG-CaCl2-mediated protoplast transformation system for Clonostachys reniana. Our results demonstrate for the first time that this species is amenable to genetic manipulation and produces transformants with genetic stability, providing a reliable platform for functional genomic research in this fungus. Using green fluorescent protein tagging, we achieved stable transformants that retained wild-type physiological traits. Crucially, our data indicated that C. reniana utilizes a distinct mycoparasitic mechanism, which differs from the well-established sequential process of adhesion, coiling, and lysis seen in C. rosea. Confocal and scanning electron microscopy revealed that C. reniana, following initial coiling and invasive structure formation, penetrates the host hyphae of Botryosphaeria dothidea. It then grows longitudinally within the hyphal lumen, absorbing nutrients and eliminating the pathogen from the inside. Furthermore, C. reniana hyphae can colonize the intercellular spaces of the stem periderm in 84K poplar (Populus alba × P. glandulosa) while displaying a distinct tissue-specific behavior in the roots by forming a mantle on the root surface resembling that of ectomycorrhizae. These findings establish C. reniana as a highly promising secondary model species within the Clonostachys genus. By uncovering a novel "internal-consumption" mycoparasitic mode, this study expands our understanding of the ecological diversity of biocontrol fungi and provides a powerful genetic toolset for future functional genomic research.

Clonostachys reniana↗

PubMed2002

Barley stripe mosaic virus-induced gene silencing in a monocot plant.

RNA silencing of endogenous plant genes can be achieved by virus-mediated, transient expression of homologous gene fragments. This powerful, reverse genetic approach, known as virus-induced gene silencing (VIGS), has been demonstrated only in dicot plant species, where it has become an important tool for functional genomics. Barley stripe mosaic virus (BSMV) is a tripartite, positive-sense RNA virus that infects many agriculturally important monocot species including barley, oats, wheat and maize. To demonstrate VIGS in a monocot host, we modified BSMV to express untranslatable foreign inserts downstream of the gammab gene, in either sense or antisense orientations. Phytoene desaturase (PDS) is required for synthesizing carotenoids, compounds that protect chlorophyll from photo-bleaching. A partial PDS cDNA amplified from barley was 90, 88 and 74% identical to PDS cDNAs from rice, maize and Nicotiana benthamiana, respectively. Barley infected with BSMV expressing barley, rice or maize PDS fragments became photo-bleached and accumulated phytoene (the substrate for PDS) in a manner similar to plants treated with the chemical inhibitor of PDS, norflurazon. In contrast, barley infected with wild-type BSMV, or BSMV expressing either N. benthamiana PDS or antisense green fluorescent protein (GFP), did not photo-bleach or accumulate phytoene. Thus BSMV silencing of the endogenous PDS was homology-dependent. Deletion of the coat protein enhanced the ability of BSMV to silence PDS. This is the first demonstration of VIGS in a monocot, and suggests that BSMV can be used for functional genomics and studies of RNA-silencing mechanisms in monocot plant species.

Base Sequence↗

PubMed2025

CRISPR-based gene knockout in the model haloarchaeon Haloferax mediterranei.

Halophilic archaea, a specialized group of extremophiles that inhabit hypersaline environments, exhibit distinctive physiological and metabolic features. Traditional genetic manipulation of these organisms, predominantly reliant on homologous recombination techniques, suffers from limitations such as complex procedures and extended timelines, which hinder functional genomics research and the development of practical applications. This study established a CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-mediated gene knockout system in the model halophilic archaeon Haloferax mediterranei. A polyethylene glycol (PEG)-mediated transformation method was used to deliver a plasmid carrying a mini-CRISPR array into H. mediterranei. The crtB gene, involved in pigment synthesis, was successfully knocked out, demonstrating the feasibility of CRISPR-based editing in H. mediterranei. To further validate the reliability and targeting accuracy of the system, the hlyR4 gene, encoding an extracellular serine protease, was also disrupted. The CRISPR-mediated gene knockout efficiency for hlyR4 reached 27%, significantly higher than the approximately 3% efficiency achieved with conventional homologous recombination. The establishment of this CRISPR-based gene knockout system provides a more efficient genetic tool for H. mediterranei and lays a new experimental foundation for exploiting microbial resources from extreme environments. In this study, H. mediterranei was selected as the model organism for haloarchaea. For the first time, we successfully constructed a CRISPR-based gene knockout system in a model halophilic archaeon. This system provides a solution for CRISPR-based gene knockout tools, which are currently unavailable in model halophilic archaea, and offers an effective tool for functional genomics studies in extremophiles.

Haloferax mediterranei↗

PubMed1989

Antithrombin: structure, genomic organization, function and inherited deficiency.

Antithrombin is a major plasma protein inhibitor of proteinases generated during blood coagulation; it plays an important role in the regulation of thrombin in blood. The anticoagulant heparin greatly accelerates the rate of inactivation of proteinases by antithrombin, predominantly through its well defined, highly specific binding reaction with the inhibitor, but also through a less strictly defined interaction with some of the proteinases (such as thrombin). There is evidence for an analogous acceleratory mechanism in vivo, that functions by the binding of antithrombin to a subpopulation of heparan sulphate proteoglycans intercalated in the surface of endothelial cells. The location and structure of the gene for antithrombin are known. Both its overall organization and the structure of the subdomains of the expressed protein can be considered in terms of their relationships to a serine proteinase inhibitor superfamily, which is believed to have evolved from a common ancestor. The region of the antithrombin gene 5' to the coding region has been characterized. Unlike other members of the serpin family, there is no TATA-like promoter sequence. Two enhancer sequences have been identified that are homologous to enhancer regions of other genes. There are two polymorphisms: an intragenic polymorphism arising from a translationally silent A to G transition in codon 305, and a length polymorphism arising from the presence of 32 bp or 108 bp non-homologous sequences 345 bp upstream from the translation initiation codon. Inherited deficiency of antithrombin is associated with familial thromboembolism. The molecular genetic basis of some subtypes of deficiency is increasingly yielding to investigation. It is interesting to note that a number of mutations have been identified in CpG dinucleotides, supporting the suggestion that this dinucleotide sequence may represent a mutation hotspot in the human genome.

Amino Acid Sequence↗

PubMed2004

Genetic mapping of EST-derived microsatellites from the diploid Gossypium arboreum in allotetraploid cotton.

To increase the numbers of microsatellites available for use in constructing a genetic map, and facilitate the use of functional genomics to elucidate fiber development and breeding in cotton, we sampled microsatellite sequences from expressed sequence tags (ESTs) transcribed during fiber elongation in the A-genome species Gossypium arboreum to evaluate their frequency of occurrence, level of polymorphism and distribution in the At and Dt subgenomes of tetraploid cotton. From among ESTs derived from G. arboreum fibers at 7-10 days post anthesis (dpa), 931 ESTs were found to contain simple sequence repeats (SSRs); 544 (58.4%) EST-SSR primer pairs were developed, and 468 (86%) amplified PCR products from allotetraploid cotton (G. hirsutumcv. TM-1 and G. barbadense cv. Hai7124). However, only 99 (18.2%) of these were found to be polymorphic and segregating in our interspecific BC1 mapping population [(TM-1xHai7124)xTM-1]. In these amplified and informative EST-SSRs, hexa- and tri-nucleotide repeat motifs were the most frequent, representing 40.1 and 30%, respectively, of the total. A total of 111 loci detected with these 99 EST-SSRs were integrated into our backbone map including 511 SSR loci. The distribution of the EST-SSRs appeared to be non-random, since 72 loci were anchored to the At and 37 to the Dt subgenome of allotetraploid cotton based on linkage tests. Interestingly, out of the 10 pairs of duplicate loci amplified, seven were mapped to the corresponding homologous linkage groups and/or chromosomes. BLASTX analysis revealed that 69 of the 99 ESTs showed significant similarities to known genes. Some genes important for fiber development, such as sucrose synthase, were mapped to corresponding chromosomes. These EST-SSRs provide structural and functional genomic information that will be useful for understanding cotton fiber development.

Base Sequence↗

PubMed2004

Mutated E-cadherin: genomic and functional characterization in thyroid cells from the KAT family.

Members of a family of thyroid cell lines (KAT) were analyzed because they expressed a higher molecular weight (135 kd) form of E-cadherin at their surface. We found that this aberrant E-cadherin is the result of a point mutation in the exon 9 donor splice site causing a skipping of exon 9 with consequent deletion of the corresponding aminoacids on E-cadherin protein. As a spin-off, we report that the various members of the KAT family share this mutation as well as the genetic background. Furthermore we found that this mutated protein leads to disturbed cell-cell adhesion although E-cadherin is still able to mediate the formation of the cadherin/ catenin complex. We also demonstrate the presence of another cell-cell adhesion complex, formed by Pcadherin and the catenins. The latter is also not able to mediate cell-cell adhesion. Although these cells lack cell-cell adhesion they are not invasive without exogenous stimulus.

Base Sequence↗

PubMed2005

A novel approach for nontargeted data analysis for metabolomics. Large-scale profiling of tomato fruit volatiles.

To take full advantage of the power of functional genomics technologies and in particular those for metabolomics, both the analytical approach and the strategy chosen for data analysis need to be as unbiased and comprehensive as possible. Existing approaches to analyze metabolomic data still do not allow a fast and unbiased comparative analysis of the metabolic composition of the hundreds of genotypes that are often the target of modern investigations. We have now developed a novel strategy to analyze such metabolomic data. This approach consists of (1) full mass spectral alignment of gas chromatography (GC)-mass spectrometry (MS) metabolic profiles using the MetAlign software package, (2) followed by multivariate comparative analysis of metabolic phenotypes at the level of individual molecular fragments, and (3) multivariate mass spectral reconstruction, a method allowing metabolite discrimination, recognition, and identification. This approach has allowed a fast and unbiased comparative multivariate analysis of the volatile metabolite composition of ripe fruits of 94 tomato (Lycopersicon esculentum Mill.) genotypes, based on intensity patterns of >20,000 individual molecular fragments throughout 198 GC-MS datasets. Variation in metabolite composition, both between- and within-fruit types, was found and the discriminative metabolites were revealed. In the entire genotype set, a total of 322 different compounds could be distinguished using multivariate mass spectral reconstruction. A hierarchical cluster analysis of these metabolites resulted in clustering of structurally related metabolites derived from the same biochemical precursors. The approach chosen will further enhance the comprehensiveness of GC-MS-based metabolomics approaches and will therefore prove a useful addition to nontargeted functional genomics research.

Automation↗

PubMed2004

Multiple-testing strategy for analyzing cDNA array data on gene expression.

An objective of many functional genomics studies is to estimate treatment-induced changes in gene expression. cDNA arrays interrogate each tissue sample for the levels of mRNA for hundreds to tens of thousands of genes, and the use of this technology leads to a multitude of treatment contrasts. By-gene hypotheses tests evaluate the evidence supporting no effect, but selecting a significance level requires dealing with the multitude of comparisons. The p-values from these tests order the genes such that a p-value cutoff divides the genes into two sets. Ideally one set would contain the affected genes and the other would contain the unaffected genes. However, the set of genes selected as affected will have false positives, i.e., genes that are not affected by treatment. Likewise, the other set of genes, selected as unaffected, will contain false negatives, i.e., genes that are affected. A plot of the observed p-values (1 - p) versus their expectation under a uniform [0, 1] distribution allows one to estimate the number of true null hypotheses. With this estimate, the false positive rates and false negative rates associated with any p-value cutoff can be estimated. When computed for a range of cutoffs, these rates summarize the ability of the study to resolve effects. In our work, we are more interested in selecting most of the affected genes rather than protecting against a few false positives. An optimum cutoff, i.e., the best set given the data, depends upon the relative cost of falsely classifying a gene as affected versus the cost of falsely classifying a gene as unaffected. We select the cutoff by a decision-theoretic method analogous to methods developed for receiver operating characteristic curves. In addition, we estimate the false discovery rate and the false nondiscovery rate associated with any cutoff value. Two functional genomics studies that were designed to assess a treatment effect are used to illustrate how the methods allowed the investigators to determine a cutoff to suit their research goals.

Amphetamine↗

PubMed2007

Identification of soluble CD14 as an endogenous agonist for Toll-like receptor 2 on human astrocytes by genome-scale functional screening of glial cell derived proteins.

Human astrocytes express a limited repertoire of Toll-like receptor (TLR) family members including TLR1-4, which are expressed on the cell surface. Also, TLR3 but not TLR4 activation on astrocytes induces expression of several factors involved in neuroprotection and down-regulation of inflammation rather than in the onset of traditional pro-inflammatory reactions. The notion that astrocyte TLR may thus play a role not only in host defense but also in tissue repair responses prompted us to examine the possibility that endogenous TLR agonists could be expressed in the human central nervous system to regulate the apparently dual astrocyte functions during trauma or inflammation. As a potential source of endogenous agonists, a cDNA library derived from several human brain tumor cell lines was used. Gene pools of this library were transfected into COS-7 cells and the expression products were screened for their ability to induce TLR activation in human primary astrocytes. The screening resulted in the identification of soluble CD14. By using a panel of TLR-transfected HEK293 cells, we found that signaling by soluble CD14 was TLR2 dependent. Moreover, the CD14-triggered TLR2-mediated response in astrocytes lead to the production of CXCL8, IL-6, and IL12p40, whereas typical TLR-induced pro-inflammatory cytokines, like TNF-alpha and IL-1beta, were not produced at detectable levels. In conclusion, our data indicate that apart from its well-known ability to act as a co-receptor for TLR-dependent signaling by peptidoglycans or LPS, soluble CD14 can also act as a direct agonist for TLR2.

Adult↗

PubMed2026

An XRE-type regulator in Streptococcus mutans plays an important role in brpA expression and oxidative stress tolerance response.

This study used a functional genomics approach to explore the role of a xenobiotic response element (XRE)-type regulator (SMU.405c) in Streptococcus mutans physiology, including the expression of biofilm regulatory protein BrpA. Results showed that deletional mutation of xre significantly reduced the ability of the deficient mutant to grow in the presence of methyl viologen, a commonly used oxidative stressor (P < 0.001). When challenged in a hydrogen peroxide killing assay, the survival rate of the ∆xre mutant was >2-log less than the parent strain after 60 min (P < 0.001). Luciferase reporter fusion assays showed that xre deficiency had no significant effect on luciferase expression when it was under the control of the intact brpA promoter, but the reporter activity increased by >6-fold (P < 0.001) when the reporter gene was fused to a brpA promoter derivative with deletion of a putative XRE-binding box. Electrophoretic mobility shift assay (EMSA) showed that recombinant XRE interacted with the brpA promoter, resulting in an electrophoretic shift of the promoter probes. In vitro transcription assay also showed that inclusion of XRE caused transcription to fall off, significantly reducing full-length brpA transcripts. RNA-seq analysis revealed that deficiency of XRE led to altered expression of >102 genes by >2-fold (P < 0.05), including 28 with increased expression, and 74 with decreased expression. Among the down-regulated were genes for DNA repair and oxidative stress tolerance response. These results suggest that XRE (SMU.405c) in S. mutans plays an important role in brpA expression and oxidative stress tolerance response.IMPORTANCEStreptococcus mutans, a keystone pathogen in human dental caries, primarily lives in the highly diverse microbiota on tooth surfaces, where the conditions are often harsh and fluctuate frequently. Locus SMU.405c was annotated to encode a xenobiotic response element (XRE)-like transcriptional regulator, but no information is available concerning the role of this protein in S. mutans pathophysiology. This study used a functional genomics approach along with molecular and transcriptomic analysis to characterize a deletional xre mutant, and the results showed that xre deficiency in S. mutans resulted in weakened oxidative stress tolerance response and alterations in transcription of >102 genes, including those known to play an important role in cell envelope biogenesis and stress tolerance response. Reporter fusion assay, electrophoretic mobility shift assay (EMSA), and in vitro transcription further demonstrated that the XRE-like regulator encoded by SMU.405c is a repressor of brpA expression and plays an important role in oxidative stress tolerance response.

Streptococcus mutans↗

PubMed1997

Oldest-old healthy brain function. The genomic potential.

There will be a remarkable increase in the number of people older than 85 years--the oldest-old--in the next 50 years. This age group is especially vulnerable to increasing disabilities, many of which are the result of the aging nervous system. Among these aging changes, the most devastating and likely to have the greatest impact on our society is the development of dementia. Since dementia is present in the majority of those who live to the current maximum of the human life span, this suggests that dementia is a normal aging event. Although the exact causes of this common cognitive failure in the oldest-old are not known, there is recent evidence from genetic studies of aging and Alzheimer disease to suggest that there are a number of susceptibility genes that may modify or delay the onset of late-life brain failure. These gene families form a natural target for devising strategies for significantly delaying the onset of late-life dementia.

Aged↗

PubMed2026

Integrative Genomic and Functional Investigation of the Multi-Layered Genetic Architecture Between Anorexia Nervosa and Bone Loss.

OBJECTIVE: Bone loss is a severe and often irreversible complication of anorexia nervosa (AN), yet the genetic mechanisms underlying this comorbidity remain underexplored. This study focuses on constructing a comprehensive genetic architecture between AN and estimated calcaneal bone mineral density (eBMD). METHOD: We applied an integrative framework incorporating genetic correlation, pleiotropic association, and causal inference across single-variant, multi-variant, and gene expression levels. Functional validation was conducted in vitro to investigate the biological role of the key candidate gene. RESULTS: Local genetic correlation analysis identified significant signals at 8p21.2 and 10q26.3, despite the lack of significant global correlation. Mendelian randomization analysis pointed to a suggestive negative causal effect of genetically predisposed AN on eBMD. Extensive pleiotropic signals were detected, particularly at 3p21.31 and 10q26.3, loci enriched with genes associated with both traits. Notably, we identified a novel pleiotropic signal near NCAM1 at 11q23.2, which was supported by multi-layered genetic evidence and confirmed through in vitro functional experiments. NCAM1, a well-established neural-associated gene, promoted osteoclastic differentiation and bone resorption when overexpressed in osteoclast precursor cells, indicating that NCAM1 possesses distinct functional roles in both neural and skeletal tissues. DISCUSSION: This study constructs a comprehensive genetic architecture underlying AN and eBMD and highlights NCAM1 as a key pleiotropic gene.

anorexia nervosa↗

PubMed1998

cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family.

We have cloned OCTN2, a new member of the organic cation transporter family, from a human placental trophoblast cell line. The hOCTN2 cDNA codes for a protein of 557 amino acids with twelve putative transmembrane domains. The octn2 gene, located on human chromosome 5q31, consists of ten exons. The OCTN2-specific transcript, 3.5 kb in size, is expressed widely in human tissues and in cell lines of human origin. At the level of amino acid sequence, OCTN2 is more closely related to OCTN1 than to OCT1, OCT2 and OCT3. When expressed heterologously in HeLa cells, OCTN2 mediates the transport of tetraethylammonium, a prototypical organic cation, in a pH-dependent manner. Several organic cations, including the neurotoxins 1-methyl-4-phenylpyridinium, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and methamphetamine, compete for the OCTN2-mediated transport process.

Amines↗