Identification of a novel frameshift mutation in a Japanese adrenoleukodystrophy patient.
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Adrenoleukodystrophy↗
Biomedical subjects
T Orii
Publications and source records attributed to T Orii.
Failure of IgG production due to a defect in the opening of the chromatin structure of I gamma 1 region in a patient with IgG and IgA deficiency.
Patients with common variable immunodeficiency (CVID) display reduced levels of two or all three of the major immunoglobulin isotypes, and the deficiency is characterized by failure of B cells to differentiate into plasma cells in many cases. A patient (14 years old, female) showed normal serum IgM levels and low serum IgG and IgA levels, including low levels of all IgG subclasses. Northern blot analysis suggested that the patient's B cells may be defective at the immunoglobulin heavy chain isotype switch. The germ-line C gamma 1 transcript was amplified from cDNA of healthy controls by the addition of recombinant IL-2 (rIL-2) to pokeweed mitogen-stimulated peripheral mononuclear cells or Staphylococcus aureus Cowan I (SAC)-stimulated IgM-producing lymphoblastoid cell lines (LCL) transformed by Epstein-Barr virus, while it was not amplified from cDNA of the patient. In the I gamma 1 region of LCL cultured with SAC plus rIL-2, the inner cytosine in the 5' C-C-G-G 3' sequence nearest the 3' site of the I gamma 1 region, at least, was not completely unmethylated in the patient. Moreover, the DNase I hypersensitive site was not induced in the patient's LCL by SAC plus rIL-2. These results indicate that the defects of the immunoglobulin heavy chain isotype switch in the patient's B cells are due to failure in the synthesis of germ-line C gamma transcripts, and this may be caused by defects in opening of the chromatin structures of specific switch regions.
Adolescent↗
IgG2 deficiency associated with defects in production of interferon-gamma; comparison with common variable immunodeficiency.
We report a novel mechanism of IgG2 deficiency. Several investigators have reported patients with IgG subclass deficiencies due to homozygous deletion of immunoglobulin heavy chain constant region genes. However, it is unclear what mechanism is responsible for IgG subclass deficiency in cases where no gene deletions have been detected and which are accompanied by recurrent infections due to aberrant immunoregulation. In the present study, we have focused our attention on production by peripheral blood mononuclear cells (PBMCs) of interferon-gamma (IFN-gamma), which is known to induce IgG2 expression. PBMCs from four patients with IgG2 deficiency and their families were studied. Mitogeninduced IFN-gamma production by PBMCs was decreased in all of the patients, although the proliferative responses of PBMCs and the percentages of CD3, CD4, and CD8 T cell subsets were not decreased. IgG2 production by PBMCs was restored upon addition of IFN-gamma and mitogen to the PBMCs of the patients with IgG2 deficiency though it was not restored in the patients with common variable immunodeficiency. We conclude that defects in production of IFN-gamma play an important role in IgG2 deficiency.
Adult↗
Aberrant patterns of immunoglobulin levels in Wiskott-Aldrich syndrome.
We have investigated IgM deficiency in Wiskott-Aldrich syndrome patients. From the assessment of T and B cell functions in pokeweed mitogen-induced immunoglobulin (Ig) production, IgM deficiency was chiefly thought to result from B cell dysfunction. The percentages of surface IgM-bearing cells were decreased in peripheral blood mononuclear cells (PBMCs) and the number of IgM-secreting cells was also decreased. Lymphoblast cell lines (LCLs) from the patients have produced IgG and IgA, but never IgM. Moreover the expression of the C mu transcript from the patients' PBMCs and their LCLs were decreased, whereas the C gamma gene was well expressed. No germ-line polymorphism existed between the patients and the controls in the C mu region, and no mutation was detected in the mu s C-terminal and the M exon by nucleotide sequencing. These suggest that the Ig heavy chain (IGHC) isotype switch may be abnormally accelerated in the patients' B cells. While the methylation patterns of the human Ig enhancer gene region were the same between the patient and the control, the methylation patterns of the I gamma 1 region showed less methylation in the patient than in the control, which may cause low IgM expression and high expression levels of other classes located downstream of the IGHC gene.
Adolescent↗
Clinical and molecular analysis of a Japanese boy with Morquio B disease.
Morquio B disease was found in a 15-year-old Japanese boy who presented with progressive generalized skeletal dysplasia without neurological manifestations. Mild keratan sulfaturia was found, and beta-galactosidase was deficient in fibroblasts. Gene analysis revealed two mutant alleles, 83Tyr-->His (Y83H) and 482Arg-->Cys (R482C). The former expressed a low enzyme activity (2-5% of normal), and the latter expressed no detectable enzyme activity.
Adolescent↗
Abnormal response to exercise, face immersion, and isoproterenol in children with the long QT syndrome.
The present study was performed to observe the change of QT interval by sympathetic stimulations in patients with the long Qt syndrome (LQTS). The study group consisted of 6 children with LQTS and 6 healthy children without QT prolongation. All LQTS patients had syncopal episodes. The QTc and delta QTc% ([QTc interval after examination-QTc interval at rest]/ QTc interval at rest x 100) by treadmill testing, face immersion, and isoproterenol were examined. One minute after peak exercise of treadmill testing, the changes in the QTc interval were not significant in either group, but delta QTc% was larger in the LQTS group than in the control group (+ 11.0 +/- 12.1% vs -2.6 +/- 3.2%; P = 0.02). The QTc interval at the shortest RR interval during face immersion was prolonged in the LQTS group (0.47 +/- 0.01 s to 0.51 +/- 0.04 s; P = 0.02), but there were no significant changes in the control group (0.40 +/- 0.03 s to 0.41 +/- 0.03 s; P = NS). delta QTc% was larger in the LQTS group than in the control group (+ 10.0 +/- 7.3% vs +1.1 +/- 5.5%; P = 0.04). In the LQTS group, the RR interval was shortened (P = 0.009) and QTc interval was prolonged (P = 0.0008) after isoproterenol infusion. These sympathetic stimulations amplified the TU abnormality in the LQTS group. By observing the TU changes caused by face immersion, we hoped to find a possible new method with which to diagnose LQTS. The combination of these examinations may be helpful in screening the borderline cases of TU abnormalities.
Adolescent↗
DNA mutation induced in the sequence upstream of the secreted MYU C-terminal coding sequence by ultraviolet irradiation in the cell line of Bloom's syndrome.
Selective IgM deficiency is commonly found in Bloom's syndrome (BS). We reported that membrane-bound mu (micron(s)) mRNA was well transcribed but secreted mu (microseconds) mRNA was not, although there was no mutation or deletion in the sequence including the microseconds C-terminal coding sequence in the patients with BS. Furthermore, we have shown previously, preferential damage to IgM production by ultraviolet (UV) irradiation of the cells of the patient. In the study described here, mutation in the sequence which is upstream of the 5' end of the microseconds C-terminal coding sequence was induced by UV irradiation in the lymphoblastoid cell line (LCL) of BS patient. These results suggest that abnormal repair of DNA damage is present in this LCL, and that preferential damage to IgM production by UV irradiation in this LCL may be due to the abnormal repair of DNA damage.
Adult↗
Methylation patterns of I epsilon region in B cells stimulated with interleukin 4 and Epstein-Barr virus in patients with a high level of serum IgE.
Human IgE synthesis requires the presence of both interleukin 4 (IL-4) and T-cells. However, it is not clear what role IL-4 and T-cells play in the induction of IgE synthesis at the level of gene regulation. B cells that were obtained from patients with a high level of serum IgE and from healthy donors were immortalized by Epstein-Barr virus. We examined IgE production of these B cells stimulated with IL-4. Supernatant IgE levels of patient's B cells cultured with or without IL-4 were higher than those of healthy donor's B cells. Our results indicated that B cells stimulated with IL-4 from patients produced IgE, germline C epsilon transcript, and S mu S epsilon recombination. The germline C epsilon transcript was dose-dependently induced in the presence of IL-4 and related to the supernatant IgE level. In B cell stimulated with IL-4 that were obtained from patients, (some of the) DNA near or within the I epsilon region was (already partly) unmethylated, unlike those from healthy donors, and there was a loss of methyl groups of the DNA upon the addition of IL-4 in B cells from both patients and normal donors. IgE synthesis of B cells stimulated with IL-4 in patients with a high level of serum IgE is due to an accessibility in the immunoglobulin heavy-chain isotype switch, and this may reflect the accessibility in synthesis of germline C epsilon transcript, which may be caused by the increase of opening chromatin structures because of their unmethylation in the I epsilon region.
Asthma↗
Genetic analysis of IgE and the IGHE, IGHEP1 and IGHEP2 genes in atopic families.
The familial occurrence of allergic diseases was studied in 478 individuals and their family members. The results showed that there was pronounced familial clustering. Total serum IgE concentrations of atopic patients and their parents were well correlated. Moreover, the concentration of specific IgE of the patients and their parents was also well correlated, suggesting that IgE production was genetically determined. To determine if major structural abnormalities of IGHE, IGHEP1 and IGHEP2 genes might lead to aberrant control and subsequent increase in IgE concentration, genomic DNAs from 55 individuals, i.e., 31 atopic patients and their family members, were examined. We detected the IGHE, IGHEP1 and IGHEP2 genes in all 55 leukocyte DNAs. We could not find any large deletions or duplications in the IGHE, IGHEP1 and IGHEP2 genes of atopic patients with high serum IgE concentrations.
Adolescent↗
Viability of partial liver graft from living donor in pigs.
For evaluation of the viability of partial liver graft from a living donor, we investigated energy production of mitochondria and radical scavenging enzyme activities in partial and whole liver transplantation in pigs. The values of adenosine triphosphate (ATP) and total adenine nucleotide (TAN) of the partial liver graft were higher than those of the whole liver graft, whereas the hypoxanthine of the partial liver graft was lower than that of the whole liver graft. There was no statistical difference in the radical scavenging enzyme activities between the two groups. The values of respiratory control ratio (RCR) in both groups were above 3.0 and there was no statistical difference. The survival rates of pigs received partial liver and whole liver graft with 2 to 3 hr cold preservation was 71% and 91%, respectively and there was no statistical difference between two groups. These results suggest that viabilities of the partial liver graft from the living donor are satisfactory enough, compared with those of whole liver graft from a cadaver.
Adenine Nucleotides↗
[Free radical generation in electron transport system of mitochondria after cold preservation in UW solution].
UNLABELLED: In the liver transplantation one of the causes of primary graft nonfunction is likely associated with lipid peroxidation at reperfusion after cold preservation. In this study, we investigated whether free radicals produced in mitochondrial electron transport system would result in lipid peroxidation after cold preservation in UW solution. MATERIALS AND METHODS: Under anesthesia, the liver of male Wistar rat was flushed via the portal vein with cold Ringer lactate, and then placed in 4 degrees C UW solution for 24 hr. After cold preservation, we examined mitochondrial respiratory control ratio (RCR), free radicals (O2-) from mitochondrial electron transport system by MCLA induced chemiluminescence, and lipid peroxidation by chemiluminescence (CL) after reoxygenation. RESULTS: RCR gradually decreased up to 24 hr preservation. O2- generation from mitochondrial electron transport system was not recognized at any length of the time after cold preservation up to 24 hr. At 6 hr, CL values were slightly higher than those of the control, but significantly decreased at 24 hr. CONCLUSION: O2(-)-generated in electron transport system of mitochondria did not increase with cold preservation up to 24 hr, therefore, the radical from mitochondria did not cause a lipid peroxidation at reperfusion injury.
Adenosine↗
T cell proliferation restricted by HLA class II molecules in patients with hen's egg allergy.
We investigated the synergistic effect of anti-HLA class II monoclonal antibodies on proliferative responses to ovalbumin (OA) of T cell line (TCL) cells from five hen's-egg-sensitive patients. Among the five patients, the proliferation of the TCL cells from two patients with AD who have a low immune reaction was restored by the anti-HLA-DQ monoclonal antibodies, and the proliferation of the TCL cells from the other three patients was inhibited by the anti-HLA-DP monoclonal antibodies. These results suggest that a component of the T cell repertoire reactive with OA in hen's-egg-sensitive patients may be restricted by HLA-DP molecules. Furthermore, in hen's-egg-sensitive patients with AD who have a low immune reaction, low responsiveness may be regulated by HLA-DQ molecules.
Animals↗
Expression of surrogate light chain in common variable immunodeficiency.
VpreB and lambda-like genes encode proteins that can associate to form a light-chain-like structure, the surrogate light chain (SLC). VpreB and lambda-like genes are selectively expressed in human progenitor B and precursor B (pre-B) cells. We analyzed the expression of VpreB and lambda-like genes in seven patients with common variable immunodeficiency (CVI). Gene expression was examined in the peripheral blood mononuclear cells (PBMCs) using the polymerase chain reaction. In four CVI patients, two of whom were brothers, the expression of the VpreB gene was detectable in the PBMCs. In the brothers with CVI, the expression of the VpreB gene was also examined in bone marrow cells, where it was found to be expressed in trace amounts. A number of the brothers' bone marrow cells were stained with mu and kappa antibodies using the avidin-biotin complex method. In lambda 5-gene-deleted mice, B cell development in the bone marrow is blocked at the pre-B stage, but the blockade is leaky. We suggest that expression of the SLC is weak in patients with CVI compared with their normal counterparts, and this may be one of the underlying mechanisms of CVI.
Adult↗
Differences in lymphocyte proliferative responses to food antigens and specific IgE antibodies to foods with age among food-sensitive patients with atopic dermatitis.
BACKGROUND: Clinical symptoms of patients with food-sensitive atopic dermatitis often improve with increasing age. OBJECTIVE: To investigate this tendency and the underlying mechanism. METHODS: We selected and divided 194 food-sensitive atopic dermatitis patients into three age groups. The proliferative responses of peripheral blood mononuclear cells (PBMCs) to food antigens and specific IgE antibodies to foods then were evaluated with respect to age. We also followed up 55 food-sensitive patients with atopic dermatitis and examined their improvement ratio after 1 year. Further, we investigated changes in lymphocyte proliferative responses to food antigens and specific IgE antibodies to foods in food-sensitive patients with atopic dermatitis during elimination diets. RESULTS: Proliferative responses of PBMCs to ovalbumin of patients in the over 6-years-old group were significantly (P < .05) lower than those of the less than 1-year-old group. Proliferative responses of PBMCs to bovine serum albumin of patients in the over 6-years-old group were significantly (P < .05) lower than those in the 1 to 5-year-old group and in the less than 1-year-old group. RAST values for hen egg in the over 6-years-old group were significantly (P < .05) lower than those for the less than 1-year-old group. Improvement was shown by 13 of the 33 hen egg-sensitive patients with atopic dermatitis, an improvement ratio of 39%, and by 9 of the 22 cow milk-sensitive patients with atopic dermatitis, an improvement ratio of 41%. Proliferative responses of PBMCs to food antigens in food-sensitive patients with atopic dermatitis decreased rapidly after patients were placed on elimination diets. CONCLUSION: The PBMC proliferative responses to food antigens and RAST values were higher for young children and lower for older ones who suffered from food-sensitive atopic dermatitis. Oral tolerance, in addition to the development of digestive and absorptive functions, may be responsible for these immunologic changes.
Adolescent↗
[Mucopolysaccharidoses].
Mucopolysaccharidoses (MPS) are a lysosomal storage disorders caused by deficiency of several enzymes needed for degradation of mucopolysaccharides (glycosaminoglycans). Undegraded glycosaminoglycans accumulate in the cell, part of which are excreted into the urine. There are 10 known enzyme deficiencies that give rise to six distinct MPS. Despite the different enzyme defect, there is clinical similarity between different deficiencies and conversely, wide phenotypic variety among even one enzyme deficiency. Most of the cDNAs corresponding the defect enzyme as well as genomic DNA have been cloned. Mutational analyses of the patient gene have revealed the molecular basis of the disease, correlation of the genotype and phenotype and made the accurate heterozygote diagnosis feasible. Supportive management can greatly improve the quality of life and moreover, development of therapies, such as BMT, administration of recombinant enzyme and gene transfer are in progress for the patients suffering from MPS.
Animals↗
Prevalence of and risk factors for allergic diseases: comparison of two cities in Japan.
BACKGROUND: Differences in the prevalence of allergic diseases and the effects of genetic and environmental factors on these diseases in two areas of the same country have not been examined by multiple logistic regression. OBJECTIVE: To determine whether the effects of genetic and environmental factors on allergic diseases differ between two areas. METHODS: A questionnaire was distributed in March 1991 to children less than 16 years old attending kindergarten, elementary, or junior high school in two Japanese cities; Gifu, with a temperate climate, and Itoman, with a subtropical one. The number of subjects analyzed were 1243 in Gifu and 1953 in Itoman. Multiple logistic regression analysis was performed using SAS. RESULTS: The prevalence of allergic diseases and atopic dermatitis in Gifu were significantly higher than in Itoman (P < .05). In contrast, the prevalence of bronchial asthma in Itoman was significantly higher than in Gifu (P < .05). Multiple logistic regression analysis showed that in both cities children of families with allergic histories have significantly higher risk of contracting an allergic disease and atopic dermatitis. The prevalences of allergic diseases and atopic dermatitis were higher in Gifu than in Itoman, even after being controlled for genetic and environmental factors. CONCLUSIONS: The increased risk of contracting an allergic disease and atopic dermatitis for the children in Gifu may be due to such factors not included in the study as climate, eating habits, or the level of air pollution.
Adolescent↗
Overexpression rescues the mutant phenotype of L176F mutation causing beta-glucuronidase deficiency mucopolysaccharidosis in two Mennonite siblings.
Two beta-glucuronidase-deficient Mennonite siblings were found to be homozygous for a mutation in exon 3 of the beta-glucuronidase gene that produces a Leu-->Phe substitution (L176F). The siblings also have the previously described benign polymorphism, P649L. Although their cultured fibroblasts contained 1.5-2.2% of normal beta-glucuronidase activity, transient expression of the L176F/P649L cDNA in COS cells produced nearly as much enzyme activity as the wild-type control cDNA. The L176F/P649L enzyme was as stable as wild-type enzyme following endocytosis by fibroblasts and delivery to lysosomes, but was more labile to heat inactivation at 65 degrees C. To study the mutant enzyme at lower levels of expression, we stably transfected mouse mucopolysaccharidosis type VII cells with the L176F/P649L cDNA and selected single-copy cell lines. Metabolic labeling with [35S]methionine revealed that cell lines expressing the mutant enzyme activity at low levels (7-10% of the wild type) actually produced the same amount of enzyme protein as the cell lines expressing the more active wild-type enzyme. However, the cell lines expressing four times this much mutant enzyme protein produced 150-200% as much enzyme activity as the cell line expressing the single-copy wild-type cDNA. These data suggest that overexpression can drive the folding reaction or the self-association of mutant monomers to form active tetramers and, at least partially, correct the beta-glucuronidase deficiency seen at low levels of expression with certain missense mutations.
Alleles↗
Molecular cloning and nucleotide sequence of complementary DNA for human hepatic cytosolic acetoacetyl-coenzyme A thiolase.
Complementary DNA for human cytosolic acetoacetyl-CoA thiolase (CT) was cloned with the use of anti-[human CT] antibody. The human CT cDNA clone (HCT10) has a 1479-bp insert and a 1191-base open reading frame encoding 397 amino acid residues. Partial polypeptide sequences from purified human CT were present in the deduced sequence. In vivo expression analysis showed that HCT10 encoded potassium-ion non-activated acetoacetyl-CoA thiolase with no 3-ketooctanoyl-CoA thiolase activity, which is characteristic for CT. The deduced amino acid sequence has a 34-57% homology with 4 other human thiolases and 4 acetoacetyl-CoA thiolases of microorganisms.
Acetyl-CoA C-Acetyltransferase↗