ABSTRACT
OBJECTIVE@#To report on a patient with congenital muscular dystrophy (CMD) due to a missense variant of LMNA gene and explore its pathogenicity.@*METHODS@#The 1-year-and-1-month-old boy has presented with motor development delay and elevation of muscle enzymes for more than half a year. Congenital myopathy was suspected. Following muscle biopsy, HE staining, immunostaining and electron microscopy were conducted to clarify the clinical diagnosis. Meanwhile, DNA was extracted from the child and his parents' peripheral venous blood samples. Trio-whole exome sequencing (trio-WES) was carried out to detect pathogenic variant in the child. Candidate variant was verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#Both light and electron microscopy showed a large area of necrotic muscle tissues with infiltration of inflammatory cells. Immunohistochemistry revealed a large amount of muscle cells to be diffusely positive for Dysferlin. The patient's motor delays, elevations of muscle enzymes and histopathological results suggested a clinical diagnosis of CMD. A de novo missense c.1072G>A (p.E358K) variant was detected in the LMNA gene by trio-WES. The variant was unreported previously (PS2) and was absent from major allele frequency databases (PM2). It was a loss of function variant and was considered as hotspot variant in the LMNA gene (PM1) as the amino acid (E), located in position 358, was highly conserved, and change of this amino acid was found to cause destruction of the filament domain (AA: 30-386), which may result in serious damage to the intermediate filament protein. Furthermore, c.1072G>A (p. E358K) in LMNA gene was also predicted to be pathogenic based on MutationTaster, PROVEAN and PolyPhen-2 (PP3) analysis. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was classified to be likely pathogenic (PS2+PM1+PM2+PP3).@*CONCLUSION@#The child's condition may be attributed to the de novo missense c.1072 G>A (p.E358K) variant of the LMNA gene. Above discovery has expanded the variant spectrum of the LMNA gene.
Subject(s)
Humans , Infant , Male , Gene Frequency , Genomics , Lamin Type A/genetics , Muscular Dystrophies/genetics , Mutation , Exome SequencingABSTRACT
OBJECTIVE@#To explore the genetic basis for a child suspected for Say-Barber-Biesecker-Young-Simpson syndrome.@*METHODS@#Genomic DNA was extracted from peripheral blood samples of the child and her parents. Whole exome sequencing was carried out for the proband. Suspected variants were validated by Sanger sequencing. The impact of the variants was predicted by bioinformatic analysis.@*RESULTS@#The child was found to harbor a de novo missense variant c.2623C>T (p.Asp875Tyr) in exon 13 of the KAT6B gene. The variant was previously unreported, and was not recorded in the major allele frequency database and predicted to be pathogenic based on PolyPhen-2, MutationTaster and PROVEAN analysis. As predicted by UCSF chimera and CASTp software, the variant can severely impact the substrate-binding pocket of histone acetyltransferase, resulting in loss of its enzymatic activity. Based on standards and guidelines by the American College of Medical Genetics and Genomics, the variant was classified to be likely pathogenic (PS2+PM2+PP3).@*CONCLUSION@#The child's condition may be attributed to the de novo missense c.2623C>T (p.Asp875Tyr) variant of the KAT6B gene.
Subject(s)
Child , Female , Humans , Blepharophimosis , Congenital Hypothyroidism , Facies , Heart Defects, Congenital , Histone Acetyltransferases/genetics , Intellectual Disability , Joint Instability , Mutation , PhenotypeABSTRACT
Objective@#This study aimed at determining the characteristics of the glucose homeostasis and its relationship with iron overload of the patients with β-thalassemia major (β-TM).@*Method@#From Sun Yat-sen Memorial Hospital between January 2014 and December 2015, a total of 57 transfusion-dependent β-TM patients with 5-18 years old were enrolled in this study and fasting blood glucose(FBG) and insulin level, serum ferritin (SF), serum iron, transferrin, total iron binding capacity, unsaturated iron binding capacity were determined.Insulin resistance index (IRI), insulin sensitivity index and β-cell function index (BFI) were also estimated. Besides, in 36 patients cardiac T2* and liver T2* were estimated.@*Result@#(1) Four patients(7%) with β-TM were diagnosed diabetes mellitus, and 14(24%) had impaired fasting glucose. (2) The incidence of abnormal glucose metabolism was significantly different according to levels of SF and degrees of the cardiac iron overload(χ2=9.737, P<0.05; χ2=17.027, P<0.05). It rose while the level of SF increased and the degree of cardiac iron overload aggravated. (3) The incidence of abnormal glucose level was not significantly different in cases with different degree of liver iron overload.The severe group of liver iron overload had significantly higher levels of INS, HOMA-βFI, HOMA-ISI, HOMA-βFI than the non-severe group (Z=-2.434, -2.515, F=8.658, all P<0.05), while no differences were found in the level of FBG, HOMA-βFI between two groups. (4) The result of logistic regression analysis indicated that the cardiac T2* was a significant predictor for the incidence of abnormal glucose metabolism in TM patients (P=0.035, OR=1.182%, 95%CI=1.048 to 1.332).@*Conclusion@#The high prevalence of abnormal glucose metabolism in β-TM patients was mainly closely related with the internal iron overload, especially in organs.The cardiac T2* was an independent risk factor for the incidence of abnormal glucose metabolism in TM patients.
ABSTRACT
Objective To explore the effect of bone marrow mesenchymal stem cells (MSCs) on LPS-stimulated BV2 microglia in inflammatory reaction. Methods Mouse MSCs were isolated and purified by adherence screening. The routinely cultured BV2 microglia in vitro were divided into PBS control group (group A),PBS plus MSCs treatment group(group B),LPS stimulation group(group C) and LPS plus MSCs group(group D).MSCs and BV2 microglia were cultured in the transwell co-culture system for 24 hours. We observed BV2 microglia morphological changes under the microscope,detected the concentrations of NO by Griess reaction,and the level of IL-1β,TNF-αby ELISA. Results MSCs can improve the morphology of activated microglia. The concentrations of TNF-a, IL-1βand N0 in culture supernatants were increased significantly (P < 0.05) after microglia activation, however, at the present of MSCs,the concentration of these inflammatory factors declined dramaticly (P<0.05). Conclusions MSCs can significantly inhibit the activation of microglia. It may play a neuroprotective effect by reducing the inflammation of microglia. MSCs showing anti-inflammatory effects through non-direct contact with nicroglial, suggesting that MSCs outside the brain may also inhibit the activation of microglia.
ABSTRACT
AIM: To quest the relationship bwteen BDNF and seizures. METHODS: BDNF and other correlative proteins in the hippocampus of audioepileptic rat (P77PMC) have been detected by immunohistochemistry at different stages of seizures including quiet stage, preconvulsive stage, convulsive stage and postconvulsive stage. Wistar rats were served as controls. RESULTS: At quiet stage, the BDNF in the hippocampus of P77PMC were less than that of control group and stepped up after stimulation, trkB in the hippocampus of P77PMC were high at every stages, but PY20 were increased only after stimulation. NPY in the hippocampus of P77PMC were in a low level before seizures. CONCLUSION: The endogenetic BDNF may alter the excitement of P77PMC by adjusting the expression of NPY in hippocampus and activating its receptor trkB.
ABSTRACT
Neuropeptide Y (NPY) is a pancreatic polypeptide-related peptide, consisting of 36 amino acids. NPY is expressed in the nervous system widely and abundantly, mainly in the hippocampus, regulates the excitability of neurons through its receptors (Y_1, Y_2, Y_5). In recent years the research progress indicated the changes induced by seizures in the level and distribution of NPY, its receptors subtypes and their respective mRNAs in brain. The inhibitory action of NPY on glutamate-mediated neurotransmission and in seizure phenomena, suggests that one of its roles in hippocampal physiology is to modulate neuronal excitability by regu-lating glutamate release.