Cryo-EM structure of the human Asc-1 transporter complex.

The Alanine-Serine-Cysteine transporter 1 (Asc-1 or SLC7A10) forms a crucial heterodimeric transporter complex with 4F2hc (SLC3A2) through a covalent disulfide bridge. This complex enables the sodium-independent transport of small neutral amino acids, including L-Alanine (L-Ala), Glycine (Gly), and D-Serine (D-Ser), within the central nervous system (CNS). D-Ser and Gly are two key endogenous glutamate co-agonists that activate N-methyl-d-aspartate (NMDA) receptors by binding to the allosteric site. Mice deficient in Asc-1 display severe symptoms such as tremors, ataxia, and seizures, leading to early postnatal death. Despite its physiological importance, the functional mechanism of the Asc-1-4F2hc complex has remained elusive. Here, we present cryo-electron microscopy (cryo-EM) structures of the human Asc-1-4F2hc complex in its apo state, D-Ser bound state, and L-Ala bound state, resolved at 3.6 Å, 3.5 Å, and 3.4 Å, respectively. Through detailed structural analysis and transport assays, we uncover a comprehensive alternating access mechanism that underlies conformational changes in the complex. In summary, our findings reveal the architecture of the Asc-1 and 4F2hc complex and provide valuable insights into substrate recognition and the functional cycle of this essential transporter complex.

Cancer SLC6A6-mediated taurine uptake transactivates immune checkpoint genes and induces exhaustion in CD8+ T cells.

Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of CD8+ T cells. Tumor cells outcompete CD8+ T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction, thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8+ T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of cancer therapies.

Hemodynamic and Clinical Profiles of Pulmonary Arterial Hypertension Patients with GDF2 and BMPR2 Variants.

Asians have a higher carrier rate of pulmonary arterial hypertension (PAH)-related genetic variants than Caucasians do. This study aimed to identify PAH-related genetic variants using whole exome sequencing (WES) in Asian idiopathic and heritable PAH cohorts. A WES library was constructed, and candidate variants were further validated by polymerase chain reaction and Sanger sequencing in the PAH cohort. In a total of 69 patients, the highest incidence of variants was found in the BMPR2, ATP13A3, and GDF2 genes. Regarding the BMPR2 gene variants, there were two nonsense variants (c.994C>T, p. Arg332*; c.1750C>T, p. Arg584*), one missense variant (c.1478C>T, p. Thr493Ile), and one novel in-frame deletion variant (c.877_888del, p. Leu293_Ser296del). Regarding the GDF2 variants, there was one likely pathogenic nonsense variant (c.259C>T, p. Gln87*) and two missense variants (c.1207G>A, p. Val403Ile; c.38T>C, p. Leu13Pro). The BMPR2 and GDF2 variant subgroups had worse hemodynamics. Moreover, the GDF2 variant patients were younger and had a significantly lower GDF2 value (135.6 ± 36.2 pg/mL, p = 0.002) in comparison to the value in the non-BMPR2/non-GDF2 mutant group (267.8 ± 185.8 pg/mL). The BMPR2 variant carriers had worse hemodynamics compared to the patients with the non-BMPR2/non-GDF2 mutant group. Moreover, there was a significantly lower GDF2 value in the GDF2 variant carriers compared to the control group. GDF2 may be a protective or corrected modifier in certain genetic backgrounds.

Characterisation of anhydro-sialic acid transporters from mucosa-associated bacteria.

Sialic acid (Sia) transporters are critical to the capacity of host-associated bacteria to utilise Sia for growth and/or cell surface modification. While N-acetyl-neuraminic acid (Neu5Ac)-specific transporters have been studied extensively, little is known on transporters dedicated to anhydro-Sia forms such as 2,7-anhydro-Neu5Ac (2,7-AN) or 2,3-dehydro-2-deoxy-Neu5Ac (Neu5Ac2en). Here, we used a Sia-transport-null strain of Escherichia coli to investigate the function of members of anhydro-Sia transporter families previously identified by computational studies. First, we showed that the transporter NanG, from the Glycoside-Pentoside-Hexuronide:cation symporter family, is a specific 2,7-AN transporter, and identified by mutagenesis a crucial functional residue within the putative substrate-binding site. We then demonstrated that NanX transporters, of the Major Facilitator Superfamily, also only transport 2,7-AN and not Neu5Ac2en nor Neu5Ac. Finally, we provided evidence that SiaX transporters, of the Sodium-Solute Symporter superfamily, are promiscuous Neu5Ac/Neu5Ac2en transporters able to acquire either substrate equally well. The characterisation of anhydro-Sia transporters expands our current understanding of prokaryotic Sia metabolism within host-associated microbial communities.

Comprehensive Genomic Analysis Identifies a Diverse Landscape of Sideroblastic and Nonsideroblastic Iron-Related Anemias with Novel and Pathogenic Variants in an Iron-Deficient Endemic Setting.

Inherited iron metabolism defects are possibly missed or underdiagnosed in iron-deficient endemic settings because of a lack of awareness or a methodical screening approach. Hence, we systematically evaluated anemia cases (2019 to 2021) based on clinical phenotype, normal screening tests (high-performance liquid chromatography, α gene sequencing, erythrocyte sedimentation rate, C-reactive protein, and tissue transglutaminase), and abnormal iron profile by targeted next-generation sequencing (26-gene panel) supplemented with whole-exome sequencing, multiplex ligation probe amplification/mitochondrial DNA sequencing, and chromosomal microarray. Novel variants in ALAS2, STEAP3, and HSPA9 genes were functionally validated. A total of 290 anemia cases were screened, and 41 (14%) enrolled for genomic testing as per inclusion criteria. Comprehensive genomic testing revealed pathogenic variants in 23 of 41 cases (56%). Congenital sideroblastic anemia was the most common diagnosis (14/23; 61%), with pathogenic variations in ALAS2 (n = 6), SLC25A38 (n = 3), HSPA9 (n = 2) and HSCB, SLC19A2, and mitochondrial DNA deletion (n = 1 each). Nonsideroblastic iron defects included STEAP3-related microcytic anemia (2/23; 8.7%) and hypotransferrenemia (1/23; 4.3%). A total of 6 of 22 cases (27%) revealed a non-iron metabolism gene defect on whole-exome sequencing. Eleven novel variants (including variants of uncertain significance) were noted in 13 cases. Genotype-phenotype correlation revealed a significant association of frameshift/nonsense/splice variants with lower presentation age (0.8 months versus 9 years; P < 0.01) compared with missense variants. The systematic evaluation helped uncover an inherited iron defect in 41% (17/41) of cases, suggesting the need for active screening and awareness for these rare diseases in an iron-deficient endemic population.

Oculocutaneous albinism type 4: Novel compound heterozygous mutations in the SLC45A2 gene in a Chinese case.

BACKGROUND: Oculocutaneous albinism type 4 (OCA4) is a rare autosomal recessive disorder characterized by a reduction of pigmentation in skin, hair, and eyes, and OCA4 is mainly seen in the SLC45A2 gene variants. OBJECTIVE: To report a Chinese patient suspected of oculocutaneous albinism and identify the causing mutation. METHODS: Genomic DNA was extracted from the peripheral blood samples of the patient, his parents, and elder brother. Whole exome sequencing was performed in the family, and Sanger sequencing was then used to verify the mutations. RESULTS: Compound heterozygous variants, c.1304C>A (p.S435Y) and c.301C>G (p.R101G) in SLC45A2 gene, were detected in the proband, which were inherited from his father and mother respectively. Based on the ACMG guidelines, we can interpret the c.1304C>A (p.S435Y) variant as a suspected pathogenic variant and the c.301C>G (p.R101G) variant as a clinically significant unspecified variant. The diagnosis of OCA4 is confirmed. CONCLUSION: We firstly reported this case of OCA4 with the compound heterozygous variants in the SLC45A2 gene. Our findings further enrich the reservoir of SLC45A2 mutations in OCA4.

Identification and expression analysis of ATP-binding cassette (ABC) transporters revealed its role in regulating stress response in pear (Pyrus bretchneideri).

BACKGROUND: ATP-binding cassette (ABC) transporter proteins constitute a plant gene superfamily crucial for growth, development, and responses to environmental stresses. Despite their identification in various plants like maize, rice, and Arabidopsis, little is known about the information on ABC transporters in pear. To investigate the functions of ABC transporters in pear development and abiotic stress response, we conducted an extensive analysis of ABC gene family in the pear genome. RESULTS: In this study, 177 ABC transporter genes were successfully identified in the pear genome, classified into seven subfamilies: 8 ABCAs, 40 ABCBs, 24 ABCCs, 8 ABCDs, 9 ABCEs, 8 ABCFs, and 80 ABCGs. Ten motifs were common among all ABC transporter proteins, while distinct motif structures were observed for each subfamily. Distribution analysis revealed 85 PbrABC transporter genes across 17 chromosomes, driven primarily by WGD and dispersed duplication. Cis-regulatory element analysis of PbrABC promoters indicated associations with phytohormones and stress responses. Tissue-specific expression profiles demonstrated varied expression levels across tissues, suggesting diverse functions in development. Furthermore, several PbrABC genes responded to abiotic stresses, with 82 genes sensitive to salt stress, including 40 upregulated and 23 downregulated genes. Additionally, 91 genes were responsive to drought stress, with 22 upregulated and 36 downregulated genes. These findings highlight the pivotal role of PbrABC genes in abiotic stress responses. CONCLUSION: This study provides evolutionary insights into PbrABC transporter genes, establishing a foundation for future research on their functions in pear. The identified motifs, distribution patterns, and stress-responsive expressions contribute to understanding the regulatory mechanisms of ABC transporters in pear. The observed tissue-specific expression profiles suggest diverse roles in developmental processes. Notably, the significant responses to salt and drought stress emphasize the importance of PbrABC genes in mediating adaptive responses. Overall, our study advances the understanding of PbrABC transporter genes in pear, opening avenues for further investigations in plant molecular biology and stress physiology.

Boron homeostasis affects Longan yield: a study of NIP and BOR boron transporter of two cultivars.

BACKGROUND: Essential micronutrient Boron (B) plays crucial roles in plant survival and reproduction but becomes toxic in higher quantities. Although plant cells have different B transport systems, B homeostasis is mainly maintained by two transporter protein families: B exporters (BOR) and nodulin-26-like intrinsic proteins (NIP). Their diversity and differential expression are responsible for varied B tolerance among plant varieties and species. Longan is a highly admired subtropical fruit with a rising market in China and beyond. In the present study, we cultured Shixia (SX) and Yiduo (YD), two differently characterized Longan cultivars, with foliar B spray. We analyzed their leaf physiology, fruit setting, B content, and boron transporter gene expression of various tissue samples. We also traced some of these genes' subcellular localization and overexpression effects. RESULTS: YD and SX foliage share similar microstructures, except the mesophyll cell wall thickness is double in YD. The B spray differently influenced their cellular constituents and growth regulators. Gene expression analysis showed reduced BOR genes expression and NIP genes differential spatiotemporal expression. Using green fluorescent protein, two high-expressing NIPs, NIP1 and NIP19, were found to translocate in the transformed tobacco leaves' cell membrane. NIPs transformation of SX pollen was confirmed using magnetic beads and quantified using a fluorescence microscope and polymerase chain reaction. An increased seed-setting rate was observed when YD was pollinated using these pollens. Between the DlNIP1 and DlNIP19 transformed SX pollen, the former germinated better with increasing B concentrations and, compared to naturally pollinated plants, had a better seed-setting rate in YD♀ × SX♂. CONCLUSION: SX and YD Longan have different cell wall structures and react differently to foliar B spray, indicating distinct B tolerance and management. Two B transporter NIP genes were traced to localize in the plasma membrane. However, under high B concentrations, their differential expression resulted in differences in Jasmonic acid content, leading to differences in germination rate. Pollination of YD using these NIPs transformed SX pollen also showed NIP1 overexpression might overcome the unilateral cross incompatibility between YD♀ × SX♂ and can be used to increase Longan production.

Transcriptome and biochemical analysis in hexaploid wheat with contrasting tolerance to iron deficiency pinpoints multi-layered molecular process.

Iron (Fe) is an essential plant nutrient that is indispensable for many physiological activities. This study is an effort to identify the molecular and biochemical basis of wheat genotypes with contrasting tolerance towards Fe deficiency. Our physiological experiments performed at the early growth stage in cv. Kanchan (KAN) showed Fe deficiency tolerance, whereas cv. PBW343 (PBW) was susceptible. Under Fe deficient condition, KAN showed delayed chlorosis, high SPAD values, and low malondialdehyde content compared to PBW, indicative of Fe deficient condition. Comparative shoot transcriptomics revealed increased expression of photosynthetic pathway genes in PBW, further suggesting its sensitivity to Fe fluctuations. Under Fe deficiency, both the cultivars showed distinct molecular re-arrangements such as high expression of genes involved in Fe uptake (including membrane transporters) and its remobilization. Specifically, in KAN these changes lead to high root phytosiderophores (PS) biosynthesis and its release, resulting in enhanced Fe translocation index. Utilizing the non-transgenic TILLING (Targeting Induced Lesions in Genomes) technology, we identified TaZIFL4.2D as a putative PS efflux transporter. Characterization of the wheat TILLING lines indicated that TaZIFL4.2 functions in PS release and Fe acquisition, thereby imparting tolerance to Fe deficiency. Altogether, this work highlights the mechanistic insight into Fe deficiency tolerance of hexaploid wheat, thus enabling breeders to select suitable genotypes to utilize nutrients for maximum yields.

Genetic engineering low-arsenic and low-cadmium rice grain.

Rice is prone to take up the toxic elements arsenic (As) and cadmium (Cd) from paddy soil through the transporters for other essential elements. Disruption of these essential transporters usually adversely affects the normal growth of rice and the homeostasis of essential elements. Here we report on developing low-As and low-Cd rice grain through the co-overexpression of OsPCS1, OsABCC1, and OsHMA3 genes under the control of the rice OsActin1 promoter. Co-overexpression of OsPCS1 and OsABCC1 synergistically decreased As concentration in the grain. Overexpression of OsPCS1 also decreased Cd concentration in the grain by restricting the xylem-to-phloem Cd transport in node I, but paradoxically caused Cd hypersensitivity as the overproduced phytochelatins in OsPCS1-overexpressing plants suppressed OsHMA3-dependent Cd sequestration in vacuoles and promoted Cd transport from root to shoot. Co-overexpression of OsHAM3 and OsPCS1 overcame this suppression and complemented the Cd hypersensitivity. Compared with non-transgenic rice control, co-overexpression of OsABCC1, OsPCS1, and OsHMA3 in rice decreased As and Cd concentrations in grain by 92.1% and 98%, respectively, without causing any defect in plant growth and reproduction or of mineral nutrients in grain. Our research provides an effective approach and useful genetic materials for developing low-As and low-Cd rice grain.

Role of trafficking protein particle complex 2 in medaka development.

The skeletal dysplasia spondyloepiphyseal dysplasia tarda (SEDT) is caused by mutations in the TRAPPC2 gene, which encodes Sedlin, a component of the trafficking protein particle (TRAPP) complex that we have shown previously to be required for the export of type II collagen (Col2) from the endoplasmic reticulum. No vertebrate model for SEDT has been generated thus far. To address this gap, we generated a Sedlin knockout animal by mutating the orthologous TRAPPC2 gene (olSedl) of Oryzias latipes (medaka) fish. OlSedl deficiency leads to embryonic defects, short size, diminished skeletal ossification and altered Col2 production and secretion, resembling human defects observed in SEDT patients. Moreover, SEDT knock-out animals display photoreceptor degeneration and gut morphogenesis defects, suggesting a key role for Sedlin in the development of these organs. Thus, by studying Sedlin function in vivo, we provide evidence for a mechanistic link between TRAPPC2-mediated membrane trafficking, Col2 export, and developmental disorders.

Mutations in SLC45A2 lead to loss of melanin in parrot feathers.

Bird plumage coloration is a complex and multifactorial process that involves both genetic and environmental factors. Diverse pigment groups contribute to plumage variation in different birds. In parrots, the predominant green color results from the combination of 2 different primary colors: yellow and blue. Psittacofulvin, a pigment uniquely found in parrots, is responsible for the yellow coloration, while blue is suggested to be the result of light scattering by feather nanostructures and melanin granules. So far, genetic control of melanin-mediated blue coloration has been elusive. In this study, we demonstrated that feather from the yellow mutant rose-ringed parakeet displays loss of melanosome granules in spongy layer of feather barb. Using whole genome sequencing, we found that mutation in SLC45A2, an important solute carrier protein in melanin synthetic pathway, is responsible for the sex-linked yellow phenotype in rose-ringed parakeet. Intriguingly, one of the mutations, P53L found in yellow Psittacula krameri is already reported as P58A/S in the human albinism database, known to be associated with human OCA4. We further showed that mutations in SLC45A2 gene affect melanin production also in other members of Psittaculidae family such as alexandrine and plum-headed parakeets. Additionally, we demonstrate that the mutations associated with the sex-linked yellow phenotype, localized within the transmembrane domains of the SLC45A2 protein, affect the protein localization pattern. This is the first evidence of plumage color variation involving SLC45A2 in parrots and confirmation of associated mutations in the transmembrane domains of the protein that affects its localization.

Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders.

OBJECTIVE: In Norway, 89% of patients with Amyotrophic lateral sclerosis (ALS) lacks a genetic diagnose. ALS genes and genes that cause other neuromuscular or neurodegenerative disorders extensively overlap. This population-based study examined whether patients with ALS have a family history of neurological disorders and explored the occurrence of rare genetic variants associated with other neurodegenerative or neuromuscular disorders. METHODS: During a two-year period, blood samples and clinical data from patients with ALS were collected from all 17 neurological departments in Norway. Our genetic analysis involved exome sequencing and bioinformatics filtering of 510 genes associated with neurodegenerative and neuromuscular disorders. The variants were interpreted using genotype-phenotype correlations and bioinformatics tools. RESULTS: A total of 279 patients from a Norwegian population-based ALS cohort participated in this study. Thirty-one percent of the patients had first- or second-degree relatives with other neurodegenerative disorders, most commonly dementia and Parkinson's disease. The genetic analysis identified 20 possible pathogenic variants, in ATL3, AFG3L2, ATP7A, BICD2, HARS1, KIF1A, LRRK2, MSTO1, NEK1, NEFH, and SORL1, in 25 patients. NEK1 risk variants were present in 2.5% of this ALS cohort. Only four of the 25 patients reported relatives with other neurodegenerative or neuromuscular disorders. CONCLUSION: Gene variants known to cause other neurodegenerative or neuromuscular disorders, most frequently in NEK1, were identified in 9% of the patients with ALS. Most of these patients had no family history of other neurodegenerative or neuromuscular disorders. Our findings indicated that AFG3L2, ATP7A, BICD2, KIF1A, and MSTO1 should be further explored as potential ALS-causing genes.

Novel mutations in FLVCR1 cause tremors, sensory neuropathy with retinitis pigmentosa.

The mutations of the feline leukemia virus subgroup C receptor-related protein 1 (FLVCR1) cause ataxia with retinitis pigmentosa. Recent studies indicated a large variation in the phenotype of FLVCR1-associated diseases. In this report, we describe an adult male who manifested first with tremors in his third decade, followed by retinitis pigmentosa, sensory ataxia, and sensory neuropathy in his fourth decade. While retinitis pigmentosa and sensory ataxia are well-recognized features of FLVCR1-associated disease, tremor is rarely described. Whole-exome sequencing revealed novel compound heterozygous pathogenic FLVCR1 variants: c.498 G > A; p.(Trp166*) and c.369 T > G; p.(Phe123Leu). In addition, we have highlighted the ultrastructural abnormalities of the sural biopsy in this patient.

The correlation between deafness progression and SLC26A4 mutations in enlarged vestibular aqueduct patients.

BACKGROUND: The relationship between the hearing phenotype and the SLC26A4 mutation in enlarged vestibular aqueduct cases has not been fully elucidated. OBJECTIVES: To detect SLC26A4 mutation in a group of cases with enlarged vestibular aqueduct who received cochlear implantation and to analyze the correlation between the SLC26A4 genotype and the progression of deafness. MATERIALS AND METHODS: Twenty-nine enlarged vestibular aqueduct patients were selected. Using the Sanger sequence to analyze SLC26A4 gene mutations. The 29 cases were divided into group A (carrying the c.919-2A > G mutation) and group B (not carrying the c.919-2A > G mutation). The difference in the duration of deafness was analyzed between the two groups. RESULTS: The detection rate of the c.1174A > T mutation in the postlingual deafness group was 37.5%, higher than that in the prelingual deafness group (0%). The difference in the duration of deafness between groups A and B was not statistically significant by the Mann-Whitney U test (p > 0.05). CONCLUSIONS: The correlation between the SLC26A4 genotype and the duration of deafness in cases with enlarged vestibular aqueduct is not yet clear. However, the c.1174A > T mutation may be linked to delayed hearing loss and the progression of deafness may be relatively slow in some cases of c.919-2A > G mutation.

Association between genetic variants of transmembrane transporters and susceptibility to anthracycline-induced cardiotoxicity: Current understanding and existing evidence.

Anthracyclines remain the cornerstone of numerous chemotherapeutic protocols, with beneficial effects against haematological malignancies and solid tumours. Unfortunately, the clinical usefulness of anthracyclines is compromised by the development of cardiotoxic side effects, leading to dose limitations or treatment discontinuation. There is no absolute linear correlation between the incidence of cardiotoxicity and the threshold dose, suggesting that genetic factors may modify the association between anthracyclines and cardiotoxicity risk. And the majority of single nucleotide polymorphisms (SNPs) associated with anthracycline pharmacogenomics were identified in the ATP-binding cassette (ABC) and solute carrier (SLC) transporters, generating increasing interest in the pharmacogenetic implications of their genetic variations for anthracycline-induced cardiotoxicity (AIC). This review focuses on the influence of SLC and ABC polymorphisms on AIC and highlights the prospects and clinical significance of pharmacogenetics for individualised preventive approaches.

PhoU: a multifaceted regulator in microbial signaling and homeostasis.

Inorganic phosphate (Pi) is a fundamental molecule crucial for numerous biological processes, such as ATP synthesis and phospholipid formation. To prevent cellular toxicity, Pi transport is often linked to counterion transport within the bacterium. This review discusses the multifaceted functions of the PhoU protein in bacterial regulation, focusing on its role in coordinating Pi transport with counterions, controlling polyphosphate accumulation, and regulating secondary metabolite biosynthesis and DNA repair. We also explore recent findings that challenge the conventional view of PhoU simply as a negative regulator in phosphate signaling, suggesting its broader impact on bacterial physiology and stress response. Understanding the diverse functions of PhoU provides new insight into bacterial biology and offers potential therapeutic implications.

Genetic basis of the historical iron-accumulating dgl and brz mutants in pea.

The Pisum sativum (pea) mutants degenerate leaves (dgl) and bronze (brz) accumulate large amounts of iron in leaves. First described several decades ago, the two mutants have provided important insights into iron homeostasis in plants but the underlying mutations have remained unknown. Using exome sequencing we identified an in-frame deletion associated with dgl in a BRUTUS homolog. The deletion is absent from wild type and the original parent line. BRUTUS belongs to a small family of E3 ubiquitin ligases acting as negative regulators of iron uptake in plants. The brz mutation was previously mapped to chromosome 4, and superimposing this region to the pea genome sequence uncovered a mutation in OPT3, encoding an oligopeptide transporter with a plant-specific role in metal transport. The causal nature of the mutations was confirmed by additional genetic analyses. Identification of the mutated genes rationalizes many of the previously described phenotypes and provides new insights into shoot-to-root signaling of iron deficiency. Furthermore, the non-lethal mutations in these essential genes suggest new strategies for biofortification of crops with iron.

A duodenal mucosa transcriptome study identified reduced expression of a novel gene CDH18 in celiac disease.

BACKGROUND: Celiac disease (CD) a complex immune disease that affects duodenal mucosa. Identification of tissue specific biomarkers is expected to improve the existing biopsy based CD diagnosis. AIMS: To investigate the differentially expressed genes (DEGs) in duodenal mucosa tissue to identify clinically relevant gene expression pattern in CD. METHODS: Whole RNA extracted from the duodenal biopsies of three CD patients and four non-CD controls were sequenced. Significant DEGs were identified. Prioritized DEGs were validated using qRT-PCR in an independent group (CD=23; Control=26). Enriched pathways were analyzed, protein-protein interaction networks were evaluated. RESULTS: 923 DEGs comprising of 135 up-regulated, and 788 down-regulated genes, with p-value≤0.05; log2FC>2 or <-2 were identified. A novel down-regulated gene CDH18 (p = 0.03; log2FC=-0.74) was identified. Previously known CXCL9 was replicated. CDH18, a trans-membrane protein was found to interact with other CDH proteins, α/ß catenins, and other membrane transporters such as SLC and ABCB. Pathways and protein networks contributing in channel activity (p = 2.15E-12), membrane transporters (p = 2.15E-12), and cellular adhesion (p = 8.05E-6) were identified. CONCLUSIONS: CDH18, a novel DEG identified in the present study is a pivotal gene involved in maintaining epithelial membrane organization and integrity. The functional significance of lower expression of CDH18 in pathogenesis of CD warranted to be investigated. CDH18 expression could be tested for its effectiveness in diagnostic, prognostic and therapeutic purposes.