OBJECTIVE: To investigate a case of antibodies against high-frequency erythrocyte antigens and elucidate the genetic mechanism underlying the blood group. METHODS: A Lan-negative patient referred to the Zhejiang Blood Center by Quzhou Hospital of Traditional Chinese Medicine in August 2016 was selected as the study subject. A retrospective study was conducted to collect the proband's clinical data. The proband's erythrocyte antigens and unexpected serum antibodies were identified using tube saline and microcolumn agglutination anti-human globulin methods. Antibody specificity was determined by treating erythrocytes with 7 enzymes and 2 chemical reducing agents. Genomic DNA was extracted from the proband's blood sample for whole genome sequencing (WGS) and erythrocyte blood group gene analysis, with validation by Sanger sequencing. Multiple bioinformatics tools were used to analyze the pathogenicity of the variant. The rare blood group and unexpected antibody specificity were comprehensively determined based on the results of serological and genetic testing. This study has been approved by the Zhejiang Provincial Blood Center Medical Ethics Committee(Ethics No.20190201). RESULTS: The proband was a 91-year-old Han Chinese male with prostatitis, cystitis, and malnutrition in conjunct with emaciation. He had a history of multiple erythrocyte transfusions without observable adverse reactions. Prior to the most recent transfusion, major crossmatch agglutination was observed, which prompted antibody identification. Antibodies against high-frequency antigens were detected in the proband's serum, with enzyme and reducing agent treatments ruling out antibody specificities associated with 17 blood group systems, e.g., MNS, LU, KEL. WGS analysis identified 4 525 SNPs and 1 046 INDEL variants among erythrocyte blood group genes. Further screening revealed that the proband had a rare blood group due to a homozygous rs755723161 variant. This variant in the ABCB6 gene (c.459delC) has led to a frameshifting mutation (p.Trp154GlyfsTer96), resulting in the Lan-negative rare blood group with a high-frequency antigen deficiency and the production of IgG anti-Lan antibodies in the serum. CONCLUSION This study has identified anti-Lan alloantibodies in a Lan-negative patient and, for the first time, elucidated the ABCB6 gene variant underlying the Lan-negative rare blood group in the Chinese population.
Humans ; Male ; Blood Group Antigens/immunology* ; Aged, 80 and over ; Retrospective Studies ; ATP-Binding Cassette Transporters

OBJECTIVE: To explore the correlation between clinical manifestations and genetic variations in six Chinese Stargardt disease pedigrees. METHODS: Six Stargardt disease pedigrees due to ABCA4 gene variants that visited Shanxi Eye Hospital from June 2021 June 2023 were selected as the study subjects. A retrospective study method was used to collect the clinical and family history data of all members of these pedigrees. Peripheral venous blood samples of the examinees were collected, and genomic DNA was extracted for trio-WES. Candidate variants of the ABCA4 gene were verified by family Sanger sequencing. According to the "Standards and Guidelines for the Classification of Sequence Variants" (hereinafter referred to as the "ACMG Guidelines") formulated by American College of Medical Genetics and Genomics (ACMG), the variant sites of the ABCA4 gene were classified for pathogenicity. This study has been approved by the Medical Ethics Committee of Shanxi Eye Hospital (Ethics No. SXYYLL-20200620). RESULTS: From June 2021 to June 2023, 7 patients (patient 1 to 7) from families with Stargardt disease with ABCA4 variants were selected as the study subjects. The age of the patients was between 7 to 53 years old, and the age of onset was between their 6 to 15 years old. All patients had exhibited moderate-to-severe visual impairment with macular atrophy, and yellow white spots were seen in all patients except patient II2 in family 5. Optical coherence tomography (OCT) results showed that all patients' macular fovea was significantly thinner, with IS/OS or ellipsoid zone disappeared. Autofluorescence showed low autofluorescence in the macula, and abnormalities dot autofluorescence in the paramacular and periphery retina. ERG grouping classified three pedigrees as Group 3, two as Group 1, and one as Group 2. Genetic analysis results showed that all pedigrees had autosomal recessive inheritance, five had compound heterozygous variants in the ABCA4, and one had homozygous variants. In total 11 pathogenic mutations were detected in the ABCA4 gene, of which 3 were found for the first time, including p.Glu1704Gly, p.Gly1965Glu and p.Ser1531Phe. Patients carrying nonsense or frameshift mutations include patient 1 (family 1, II1), patient 2 (family 1, II2), patient 4 (family 3, II1), patient 6 (family 5, II2), and patient 7 (family 6, II1), whose clinical manifestations are more severe than those of patient 3 (family 2, II2) and patient 5 (family 4, II1), whom carried missense mutations in terms of best corrected visual acuity (BCVA) damage. CONCLUSION The ABCA4 gene variations may be the genetic cause of the Stargardt disease in this study, and the discovery of the ABCA4 gene p.Glu1704Gly, p.Gly1965Glu, p.Ser1531Phe variants has enriched the mutational spectrum of Stargardt disease.
Adolescent ; Adult ; Child ; Female ; Humans ; Male ; Middle Aged ; Young Adult ; ATP-Binding Cassette Transporters/genetics* ; China ; Genetic Variation ; Macular Degeneration/congenital* ; Mutation ; Pedigree ; Retrospective Studies ; Stargardt Disease/genetics* ; East Asian People/genetics*

OBJECTIVE: To investigate the clinical features and pathogenesis of a child with Stargardt disease caused by variants of ABCA4 gene. METHODS: A child presented at Shenzhen Eye Hospital between September 5, 2020, and April 3, 2023 was selected as the study subject. Clinical data of the child were collected. Whole exome sequencing was performed on peripheral blood samples from the child and his parents. Candidate variants were validated by Sanger sequencing and bioinformatic analysis. This study was approved by the Medical Ethics Committee of Shenzhen Eye Hospital (Ethics No.: 2022KYPJ072). RESULTS: The child was a 10-year-old male presenting with uncorrected visual acuity of 0.1 in both eyes without improvement with refractive correction. Fundus photography showed diffusely distributed yellow-white flecks in the macular region. FAF revealing central hypofluorescence surrounded by a hyperfluorescent ring, and OCT demonstrating significant foveal thinning (right eye: 45 μm; left eye: 50 μm) with ellipsoid zone disruption. Whole exome sequencing and Sanger sequencing revealed that the child has harbored compound heterozygous variants of the ABCA4 gene, namely c.2384G>T (p.Gly795Val) and c.2903G>A (p.Arg968Glu), which were inherited from his phenotypically normal parents and consistent with an autosomal recessive inheritance. This specific combination of the variants was previously unreported. According to the guidelines from the American College of Medical Genetics and Genomics (ACMG) guidelines, both variants were classified as likely pathogenic (PM2_Supporting+PM3+PP3+PP4; PM1+PM2_Supporting+PP3+PP4). CONCLUSION The novel compound heterozygous variants of the ABCA4 gene probably underlay the genetic etiology of Stargardt disease type 1 in this child. Above finding has expanded the mutational spectrum of the ABCA4 gene among the Chinese population and provided further evidence for understanding the genetic heterogeneity and genotype-phenotype correlation of the Stargardt disease.
Humans ; Male ; Child ; ATP-Binding Cassette Transporters/genetics* ; Stargardt Disease/genetics* ; Heterozygote ; Mutation ; Exome Sequencing ; Macular Degeneration/congenital*

OBJECTIVE: To explore the clinical and genetic characteristics of five fetuses with Harlequin ichthyosis (HI). METHODS: Five fetuses with HI diagnosed at Guangdong Women and Children Hospital between 2017 and 2024 were selected as study subjects. Clinical and laboratory data were collected and reviewed. Whole exome sequencing (WES) was carried out, and candidate variants were verified by bioinformatic analysis. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 202401024). RESULTS: The five fetuses had presented with ectropion, eclabium and contracture and flexion of fingers and toes. WES revealed that all had harbored compound heterozygous or homozygous variants of the ABCA12 gene. Among the eight types of variants, five were unreported previously. CONCLUSION The compound heterozygous or homozygous variants of the ABCA12 gene probably underlay the HI in the five fetuses. Clinicians should be vigilant about the possibility of HI in fetus with ectropion, eclabium, and contracture and flexion of fingers and toes.
Humans ; Ichthyosis, Lamellar/genetics* ; Female ; ATP-Binding Cassette Transporters/genetics* ; Pregnancy ; Genotype ; Phenotype ; Exome Sequencing ; Fetus ; Mutation ; Male ; Adult

Aromatic compounds are a class of organic compounds with benzene ring(s). Aromatic compounds are hardly decomposed due to its stable structure and can be accumulated in the food cycle, posing a great threat to the ecological environment and human health. Bacteria have a strong catabolic ability to degrade various refractory organic contaminants (e.g., polycyclic aromatic hydrocarbons, PAHs). The adsorption and transportation are prerequisites for the catabolism of aromatic compounds by bacteria. While remarkable progress has been made in understanding the metabolism of aromatic compounds in bacterial degraders, the systems responsible for the uptake and transport of aromatic compounds are poorly understood. Here we summarize the effect of cell-surface hydrophobicity, biofilm formation, and bacterial chemotaxis on the bacterial adsorption of aromatic compounds. Besides, the effects of outer membrane transport systems (such as FadL family, TonB-dependent receptors, and OmpW family), and inner membrane transport systems (such as major facilitator superfamily (MFS) transporter and ATP-binding cassette (ABC) transporter) involved in the membrane transport of these compounds are summarized. Moreover, the mechanism of transmembrane transport is also discussed. This review may serve as a reference for the prevention and remediation of aromatic pollutants.
Humans ; Adsorption ; Bacteria/metabolism* ; Organic Chemicals ; Biological Transport ; ATP-Binding Cassette Transporters ; Polycyclic Aromatic Hydrocarbons/metabolism*

The adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter, IrtAB, plays a vital role in the replication and viability of Mycobacterium tuberculosis (Mtb), where its function is to import iron-loaded siderophores. Unusually, it adopts the canonical type IV exporter fold. Herein, we report the structure of unliganded Mtb IrtAB and its structure in complex with ATP, ADP, or ATP analogue (AMP-PNP) at resolutions ranging from 2.8 to 3.5 Å. The structure of IrtAB bound ATP-Mg2+ shows a "head-to-tail" dimer of nucleotide-binding domains (NBDs), a closed amphipathic cavity within the transmembrane domains (TMDs), and a metal ion liganded to three histidine residues of IrtA in the cavity. Cryo-electron microscopy (Cryo-EM) structures and ATP hydrolysis assays show that the NBD of IrtA has a higher affinity for nucleotides and increased ATPase activity compared with IrtB. Moreover, the metal ion located in the TM region of IrtA is critical for the stabilization of the conformation of IrtAB during the transport cycle. This study provides a structural basis to explain the ATP-driven conformational changes that occur in IrtAB.
Siderophores/metabolism* ; Iron/metabolism* ; Mycobacterium tuberculosis/metabolism* ; Cryoelectron Microscopy ; Adenosine Triphosphate/metabolism* ; ATP-Binding Cassette Transporters

OBJECTIVE: To investigate the effects of tanshinone IIA on apoptosis and autophagy induced by hypoxia/reoxygenation in H9C2 cardiomyocytes and its mechanism. METHODS: H9C2 cardiomyocytes in logarithmic growth phase were divided into control group, hypoxia/reoxygenation model group and tanshinone IIA low-dose, medium-dose and high-dose groups (50, 100, 200 mg/L tanshinone IIA were treated after hypoxia/reoxygenation respectively). The dose with good therapeutic effect was selected for follow-up study. The cells were divided into control group, hypoxia/reoxygenation model group, tanshinone IIA+pcDNA3.1-NC group and tanshinone IIA+pcDNA3.1-ABCE1 group. The cells were transfected with the overexpressed plasmids pcDNA3.1-ABCE1 and pcDNA3.1-NC and then treated accordingly. Cell counting kit-8 (CCK-8) was used to detect H9C2 cell activity in each group. The apoptosis rate of cardiomyocytes was detected by flow cytometry. The ATP-binding cassette transporter E1 (ABCE1), apoptosis-related proteins Bcl-2 and Bax, caspase-3, autophagy-related proteins Beclin-1, microtubule-associated protein 1 light chain 3 (LC3II/I) and p62 mRNA expression level of H9C2 cells in each group were detected by real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-qPCR). The protein expression levels of the above indexes in H9C2 cells were detected by Western blotting. RESULTS: (1) Cell activity and ABCE1 expression: tanshinone IIA inhibited the activity of H9C2 cells induced by hypoxia/reoxygenation, and the effect was significant at medium-dose [(0.95±0.05)% vs. (0.37±0.10)%, P < 0.01], mRNA and protein expression of ABCE1 were significantly reduced [ABCE1 mRNA (2^-ΔΔCt): 2.02±0.13 vs. 3.74±0.17, ABCE1 protein (ABCE1/GAPDH): 0.46±0.04 vs. 0.68±0.07, both P < 0.05]. (2) Expression of apoptosis-related proteins: medium-dose of tanshinone IIA inhibited the apoptosis of H9C2 cells induced by hypoxia/reoxygenation [apoptosis rate: (28.26±2.52)% vs. (45.27±3.07)%, P < 0.05]. Compared with the hypoxia/reoxygenation model group, medium-dose of tanshinone IIA significantly down-regulated the protein expression of Bax and caspase-3 in H9C2 cells induced by hypoxia/reoxygenation, and significantly up-regulated the protein expression of Bcl-2 [Bax (Bax/GAPDH): 0.28±0.03 vs. 0.47±0.03, caspase-3 (caspase-3/GAPDH): 0.31±0.02 vs. 0.44±0.03, Bcl-2 (Bcl-2/GAPDH): 0.53±0.02 vs. 0.37±0.05, all P < 0.05]. (3) Expression of autophagy-related proteins: compared with the control group, the positive rate of LC3 in the hypoxia/reoxygenation model group was significantly increased, while the positive rate of LC3 in the medium-dose of tanshinone IIA group was significantly decreased [(20.67±3.09)% vs. (42.67±3.86)%, P < 0.01]. Compared with hypoxia/reoxygenation model group, medium-dose of tanshinone IIA significantly down-regulated Beclin-1, LC3II/I and p62 protein expressions [Beclin-1 (Beclin-1/GAPDH): 0.27±0.05 vs. 0.47±0.03, LC3II/I ratio: 0.24±0.05 vs. 0.47±0.04, p62 (p62/GAPDH): 0.21±0.03 vs. 0.48±0.02, all P < 0.05]. (4) Expression of apoptosis and autophagy related proteins after transfection with overexpressed ABCE1 plasmid: compared with tanshinone IIA+pcDNA3.1-NC group, the protein expression levels of Bax, caspase-3, Beclin-1, LC3II/I and p62 in tanshinone IIA+pcDNA3.1-ABCE1 group were significantly up-regulated, while the protein expression level of Bcl-2 was significantly down-regulated. CONCLUSIONS 100 mg/L tanshinone IIA could inhibit autophagy and apoptosis of cardiomyocytes by regulating the expression level of ABCE1. So, it protects H9C2 cardiomyocytes injury induced by hypoxia/reoxygenation.
Humans ; Apoptosis ; ATP-Binding Cassette Transporters/metabolism* ; Autophagy ; bcl-2-Associated X Protein/metabolism* ; Beclin-1/metabolism* ; Caspase 3/metabolism* ; Follow-Up Studies ; Myocytes, Cardiac ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; RNA, Messenger/metabolism* ; Cell Hypoxia

Sterols are a class of cyclopentano-perhydrophenanthrene derivatives widely present in living organisms. Sterols are important components of cell membranes. In addition, they also have important physiological and pharmacological activities. With the development of synthetic biology and metabolic engineering technology, yeast cells are increasingly used for the heterologous synthesis of sterols in recent years. Nevertheless, since sterols are hydrophobic macromolecules, they tend to accumulate in the membrane fraction of yeast cells and consequently trigger cytotoxicity, which hampers the further improvement of sterols yield. Therefore, revealing the mechanism of sterol transport in yeast, especially understanding the working principle of sterol transporters, is vital for designing strategies to relieve the toxicity of sterol accumulation and increasing sterol yield in yeast cell factories. In yeast, sterols are mainly transported through protein-mediated non-vesicular transport mechanisms. This review summarizes five types of sterol transport-related proteins that have been reported in yeast, namely OSBP/ORPs family proteins, LAM family proteins, ABC transport family proteins, CAP superfamily proteins, and NPC-like sterol transport proteins. These transporters play important roles in intracellular sterol gradient distribution and homeostasis maintenance. In addition, we also review the current status of practical applications of sterol transport proteins in yeast cell factories.
Saccharomyces cerevisiae/genetics* ; Sterols ; Phytosterols ; Biological Transport ; ATP-Binding Cassette Transporters/genetics*

ATP-Binding Cassette Transporters/genetics* ; Follow-Up Studies ; Humans ; Infant ; Lung ; Lung Diseases, Interstitial/genetics*

ATP-binding cassette(ABC) transporters are one of the largest protein families in organisms, with important effects in regulating plant growth and development, root morphology, transportation of secondary metabolites and resistance of stress. Environmental stress promotes the biosynthesis and accumulation of secondary metabolites, which determines the quality of medicinal plants. Therefore, how to improve the accumulation of secondary metabolites has been a hotspot in studying medicinal plants. Many studies have showed that ABC transporters are extremely related to the transportation and accumulation of secondary metabolites in plants. Recently, with the great development of genomics and transcriptomic sequencing technology, the regulatory mechanisms of ABC transporters on secondary metabolites have attached great attentions in medicinal plants. This paper reviewed the mechanisms of different groups of ABC transporters in transporting secondary metabolites through cell membranes. This paper provided key theoretical basis and technical supports in studying the mechanisms of ABC transporters in medicinal plant, and promoting the accumulation of secondary metabolites, in order to improve the quality of medicinal plants.
ATP-Binding Cassette Transporters/metabolism* ; Biological Transport ; Plant Development ; Plants, Medicinal/metabolism* ; Stress, Physiological