OBJECTIVE: To explore the clinical characteristics and genetic basis of two brothers featuring X-linked alpha thalassemia mental retardation (ATR-X) syndrome. METHODS: An infant who had presented at the Qilu Children's Hospital in 2020 for unstable upright head and inability to roll over and his family were selected as the study subjects. The clinical features of the child and one of his brothers were summarized, and their genomic DNA was subjected to targeted capture and next generation sequencing (NGS). RESULTS: The brothers had presented with mental retardation and facial dysmorphisms. NGS revealed that they had both harbored a hemizygous c.5275C>A variant of the ATRX gene located on the X chromosome, which was inherited from their mother. CONCLUSION The siblings were diagnosed with ATR-X syndrome. The discovery of the c.5275C>A variant has enriched the mutational spectrum of the ATRX gene.
Humans ; Infant ; Male ; alpha-Thalassemia/diagnosis* ; Ataxia Telangiectasia Mutated Proteins/genetics* ; East Asian People ; Intellectual Disability/genetics* ; Mental Retardation, X-Linked/diagnosis* ; Pedigree ; X-linked Nuclear Protein/genetics*

Objective: To detect of gene expression and genotype of the ataxia telangiectasia mutated (ATM) from coal workers' pneumoconiosis (CWP) , It is explored whether CWP is related to ATM gene. Methods: In October 2020, the relevant information of 264 subjects who received physical examination or medical treatment in the Department of occupational diseases of Guiyang public health treatment center from January 2019 to September 2020 was collected. Through the occupational health examination, 67 healthy people with no history of exposure to occupational hazards were selected as the healthy control group; The coal miners with more than 10 years of coal dust exposure history and small shadow in the lung but not up to the diagnostic criteria were the dust exposure control group, a total of 66 people; The patients with the same history of coal dust exposure and confirmed stage I were coal worker's pneumoconiosis stage I group, a total of 131 people. The expression of ATM was detected by QRT PCR. ATM rs189037 and rs1801516 were genotyped by massarray. Results: There was significant difference in the expression of ATM among the groups (P<0.05) ; Compared with the healthy control group, the expression of ATM in the dust exposed control group was significantly increased (P<0.05) . With the occurrence and development of CWP, the GG of rs189037 wild type decreased, the GA of mutant heterozygote and AA of homozygote increased, but the difference was not statistically significant (P>0.05) ; Rs1801516 wild type GG and mutant heterozygote GA had no significant changes (P>0.05) . There were significant differences in age, neutrophils and basophils among rs189037 groups (all P<0.05) . There were no significant differences in blood pressure, eosinophils, lymphocytes, monocytes, smoking and drinking history among rs189037 groups (all P>0.05) . Compared with wild-type GG, the or of mutant heterozygotes and homozygotes increased, but the differences were not statistically significant (P>0.05) . Conclusion: ATM gene may be one of the early activation genes of CWP and rs189037 may be the functional loci which affects gene expression. ATM gene is related to inflammatory response, Neutrophils and basophils have an impact on the development of CWP.
Anthracosis/genetics* ; Ataxia Telangiectasia ; Ataxia Telangiectasia Mutated Proteins/genetics* ; China ; Coal ; Coal Mining ; Humans ; Miners ; Pneumoconiosis/epidemiology* ; Polymorphism, Single Nucleotide

OBJECTIVE: Two brothes with Seckel's syndrome 1(SCKL1) were reported and a literature review was carried to provide clinical and genetic information of this rare disease. METHODS: Clinical data of the two children were collected, and the peripheral blood was extracted for whole exome sequencing. Literature of the disease were reviewed. RESULTS: The two patients were 11 years and 9.5 years old when examined for short stature. They presented with intrauterine growth retardation, intellectual disability, microcephaly, birdhead-like face and coffee au lait spots. The bone age was more than 2 years behind the chronical age and the growth hormone levels were normal. Whole exome sequencing revealed novel compound heterozygous variants c.1A>G (p.M1?) and c.4853-18A>G of ART gene in both children. CONCLUSION Children with prenatal onset short stature, developmental delay, microcephaly and special facial featuresshould be considered for the possibility of Seckel's syndrome, whole exome sequencing could help to confirm the clinical diagnosis.
Ataxia Telangiectasia Mutated Proteins/genetics* ; Child ; Dwarfism/genetics* ; Humans ; Intellectual Disability/genetics* ; Male ; Microcephaly/genetics* ; Siblings ; Whole Exome Sequencing

OBJECTIVE: To investigate the effects of chemotherapeutic agents widely used in clinical practice on major histocompatibility complex class I-related chain A and B (MICA/B) expression in breast cancer cells, and to explore the molecular mechanisms involved. METHODS: We examined MICA/B mRNA and surface protein expressions in breast cancer cells treated with chemotherapeutic agents by real-time RT-PCR and flow cytometry respectively. The blocking effects of ataxia telangiectasia mutated and Rad3-related kinase (ATM/ATR) inhibitor caffeine and nuclear factor κB (NF-κB) inhibitor pynolidine dithiocarbamate (PDTC) on etoposide-upregulated MICA/B mRNA and surface protein expressions were investigated. Electrophoretic mobility shift assay (EMSA) was taken to investigate whether etoposide enhanced the binding of NF-κB to MICA/B gene promoter. RESULTS: Three topoisomerase inhibitors etoposide, camptothecin and doxorubicine upregulated MICA and MICB mRNA expressions in breast cancer cell MCF-7. Comparing to no-drug-treated cells, MICA mRNA levels increased to (1.68±0.17), (2.54±0.25) and (3.42±0.15) fold, and levels of MICB mRNA increased to (1.82±0.24), (1.56±0.05) and (5.84±0.57) fold respectively in cancer cells treated by etoposide at the concentrations of 5, 20 and 100 μmol/L (P<0.05). MICA and MICB mRNA levels also increased significantly when MCF-7 cells were incubated with camptothecin or doxorubicine at the specific concentrations (P<0.05). MICB mRNA expression also increased slightly in another breast cancer cell SK-BR-3 treated by topoisomerase II inhibitors etoposide and camptothecin (P<0.05). Furthermore, etoposide and camptothecin upregulated MICA/B surface protein expression in MCF-7 cells (P<0.05), and the upregulation was found in both living and apoptotic cells. Our study showed that etoposide induced-MICA/B expression in MCF-7 was inhibited by caffeine at different concentrations. When cancer cells were treated by caffeine with 1, 5 and 10 mmol/L, MICA mRNA levels decreased from (3.75±0.25) to (0.89±0.05), (0.81±0.02) and (0.48±0.04) fold respectively (P<0.001), and MICB mRNA levels decreased from (6.85±0.35) to (1.36±0.13), (0.76±0.06) and (0.56±0.03) fold (P<0.05), while MICA/B protein levels decreased from (3.42±0.05) to (1.32±0.03), (1.21±0.06) and (1.14±0.03) fold (P<0.001), indicating that etoposide-induced MICA/B expression was inhibited by ATM/ATR inhibitor. Similarly, NF-κB inhibitor PDTC also inhibited MICA/B mRNA and protein expressions induced by etoposide significantly when MCF-7 cells were incubated with PDTC at the concentrations of 10, 50 and 100 μmol/L (P<0.05), indicating that NF-κB was also involved in this process. EMSA showed that the binding of NF-κB to MICA/B promoter enhanced in MCF-7 cells after etoposide treatment. CONCLUSION Topoisomerase inhibitor increased MICA/B mRNA and protein expressions in breast cancer cells, indicating that chemotherapeutic agents might increase the recognizing and killing ability of immunocytes to breast cancer cells. ATM/ATR and NF-κB pathways might be involved in it.
Antineoplastic Agents/pharmacology* ; Ataxia Telangiectasia Mutated Proteins/physiology* ; Breast Neoplasms/genetics* ; Cell Line, Tumor ; Doxorubicin ; Etoposide/pharmacology* ; Histocompatibility Antigens Class I ; Humans ; I-kappa B Proteins ; NF-kappa B/physiology* ; RNA, Messenger ; Topoisomerase Inhibitors ; Up-Regulation

OBJECTIVETo investigate miR-181a function and regulation mechanism by identifying miR-181a target genes in acute myeloid leukemia (AML).

METHODSThe HL-60 cells of human AML was transfected by small molecular analog miR-181a, the cell proliferation was detected by CCK-8 method after electroporation in HL-60 cell lines. Target genes of miR-181a were predicted and analyzed by the bioinformatics software and database. Target genes were confirmed by HL-60 cell line and the patient leukemia cells.

RESULTSOverexpressed miR-181a in HL-60 cell line significantly enhanced cell proliferation compared with that in control (P < 0.05). Dual luciferase reporter gene assay showed that miR-181a significantly suppressed the reporter gene activity containing ATM 3'-UTR by about 56.8% (P < 0.05), but it didn't suppress the reporter gene activity containing 3'-UTR ATM mutation. Western blot showed that miR-181a significantly downregulated the expression of ATM in human leukemia cells. It is also found that miR-181a was significantly increased in AML, which showed a negative correlation with ATM expression.

CONCLUSIONmiR-181a promotes cell proliferation in AML by regulating the tumor suppressor ATM, thus it plays the role as oncogene in pathogenesis of AML.

Ataxia Telangiectasia Mutated Proteins ; metabolism ; Cell Proliferation ; Down-Regulation ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute ; metabolism ; pathology ; MicroRNAs ; genetics ; metabolism ; Transfection

OBJECTIVETo detect the expression of SMG-1, ATM and P53 in laryngeal squamous cell carcinoma (LSCC) and their correlation with the clinicopathological features and outcomes of the patients.

METHODSSixty-three specimens of surgically resected LSCC tissues and 30 specimens of adjacent normal tissue were examined for the expressions of ATM, SMG-1 and P53 using immunohistochemistry. The correlation of ATM, SMG-1 and P53 expressions with the clinicopathological factors and their interactions were analyzed.

RESULTSThe positive expression rates of SMG-1, ATM and P53 in LSCC were 36.5% (23/63) , 41.3% (26/63) and 57.1% (36/63) respectively, significantly different from those in the adjacent tissue (73.3%, 83.3% and 20.0%, respectively; P<0.05). The expression of SMG-1 in LSCC was positively correlated with the pathological grade and T stage of the tumors (P<0.05), and ATM and P53 were not related to the clinicopathological factors (P>0.05). The 5-year survival rate of patients negative for SMG-1 expression was significantly higher than that of SMG-1-positive patients (P<0.05). The expression of SMG-1 was negatively correlated with that of P53 (r=-0.476, P<0.01).

CONCLUSIONSMG-1, ATM and P53 are closely related to the occurrence of LSCC. SMG-1 expression is an important factor associated with the clinicopathological features and prognosis of LSCC patients, and may play an important role in the development of LSCC by regulating P53 expression.

Ataxia Telangiectasia Mutated Proteins ; genetics ; metabolism ; Carcinoma, Squamous Cell ; genetics ; metabolism ; Humans ; Immunohistochemistry ; Laryngeal Neoplasms ; genetics ; metabolism ; Lymphatic Metastasis ; Phosphatidylinositol 3-Kinases ; genetics ; metabolism ; Prognosis ; Survival Rate ; Tumor Suppressor Protein p53 ; genetics ; metabolism

Cardiovascular disease is a severe threat to human health and life. Among many risk factors of cardiovascular disease, genetic or gene-based ones are drawing more and more attention in recent years. Accumulated evidence has demonstrated that the loss or mutation of ataxia telangiectasia mutated (ATM) gene can result in DNA damage repair dysfunctions, telomere shortening, decreased antioxidant capacity, insulin resistance, increased lipid levels, etc., and thus can promote the occurrence of cardiovascular risk factors, such as aging, atherosclerosis and metabolic syndrome. In this review, we discusses the possible mechanisms between ATM gene and cardiovascular risk factors, which could be helpful to the related research and clinical application.
Aging ; Ataxia Telangiectasia Mutated Proteins ; genetics ; Cardiovascular Diseases ; genetics ; DNA Damage ; DNA Repair ; Humans ; Mutation ; Risk Factors

No abstract available.
Adolescent ; Ataxia Telangiectasia/*genetics ; Ataxia Telangiectasia Mutated Proteins/*genetics ; Base Sequence ; Chromosome Inversion ; Chromosomes, Human, Pair 14/genetics ; Chromosomes, Human, Pair 7/genetics ; DNA Mutational Analysis ; Female ; Humans ; Karyotyping ; Magnetic Resonance Imaging ; Mutation ; RNA Splicing ; Translocation, Genetic

Ataxia telangiectasia mutated (ATM) kinase plays an essential role in the maintenance of genomic stability. ATM-deficient (ATM(-/-)) mice exhibit hematopoietic stem cell (HSC) dysfunction and a high incidence of lymphoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM(-/-) HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM(-/-) mice. Instead, ATM and Gadd45a double knockout (ATM(-/-) Gadd45a(-/-)) HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM(-/-) HSCs in HSC transplantation experiments. Further experiments revealed that the aggravated defect of ATM(-/-) Gadd45a(-/-) HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signaling pathway. Additionally, ATM(-/-) Gadd45a(-/-) mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM(-/-) mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which subsequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM(-/-) HSCs.
Animals ; Ataxia Telangiectasia Mutated Proteins ; genetics ; B-Lymphocytes ; pathology ; Cell Cycle Proteins ; genetics ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor p21 ; metabolism ; DNA Damage ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells ; metabolism ; pathology ; Leukemia ; genetics ; pathology ; Lymphoma ; genetics ; pathology ; Mice, Knockout ; Neoplasm Metastasis ; Nuclear Proteins ; genetics ; T-Lymphocytes ; pathology ; Tumor Suppressor Protein p53 ; metabolism

Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder. It is characterized by early-onset, progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival telangiectasias, immunodeficiency, and an increased risk of malignancy. Although A-T is known to be the most common cause of progressive cerebellar ataxia in childhood, there have been no confirmed cases in Korea. We report the clinical and genetic findings of Korean siblings who presented with limb and truncal ataxia, oculomotor apraxia, choreoathetosis, and telangiectasias of the eyes. Sequence analysis of the ataxia-telangiectasia mutated (ATM) gene revealed a known missense mutation (c.8546G>C; p.Arg2849Pro) and a novel intronic variant of intron 17 (c.2639-19_2639-7del13). Reverse-transcription PCR and sequencing analysis revealed that the c.2639-19_2639-7del13 variant causes a splicing aberration that potentiates skipping exon 18. Because A-T is quite rare in Korea, the diagnosis of A-T in Korean patients can be delayed. We recommend that a diagnosis of A-T should be suspected in Korean patients exhibiting the clinical features of A-T.
Asian Continental Ancestry Group/*genetics ; Ataxia Telangiectasia/diagnosis/*genetics ; Ataxia Telangiectasia Mutated Proteins/*genetics ; Child ; Female ; Heterozygote ; Humans ; Introns ; Male ; Mutation, Missense ; Pedigree ; Republic of Korea ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Analysis, DNA ; Siblings