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Biomedical subjects

F Endo

Publications and source records attributed to F Endo.

At least 73 records · Page 4Linked to original sources
PubMed1998

Tyrosinemia type I-like disease: a possible manifestation of 3-oxo-delta 4-steroid 5 beta-reductase deficiency.

BACKGROUND: It has been suggested that quantitative analysis of urinary bile acids may help to distinguish primary 3-oxo-delta 4-steroid 5 beta-reductase deficiency from the excretion of 3-oxo-delta 4 bile acids that occurs as a result of liver damage. METHODS: Urinary bile acids were quantitatively analyzed by gas chromatography-mass spectrometry in four Japanese patients with severe neonatal cholestasis associated with hypertyrosinemia without urinary succinylacetone (i.e. tyrosinemia type I-like disease). These four patients represented sporadic cases. RESULTS: Large amounts of 3-oxo-delta 4 bile acids were detected, which comprised greater than 80% of the total urinary bile acids. Small amounts of allo-bile acids and primary bile acids were also detected, comprising less than 1% and 15% of the total urinary bile acids, respectively. CONCLUSIONS: It was suspected that these four patients had a primary 3-oxo-delta 4-steroid 5 beta-reductase deficiency. However, it is possible that some patients in this study may have had a secondary 3-oxo-delta 4-steroid 5 beta-reductase deficiency, caused by idiopathic neonatal cholestatic liver failure.

Amino Acid Metabolism, Inborn Errors↗
PubMed1997

Complete rescue of lethal albino c14CoS mice by null mutation of 4-hydroxyphenylpyruvate dioxygenase and induction of apoptosis of hepatocytes in these mice by in vivo retrieval of the tyrosine catabolic pathway.

Hereditary tyrosinemia 1 (HT1) is characterized by progressive liver damage, from infancy, and by a high risk for hepatocellular carcinoma. HT1 is due to mutations in the fumarylacetoacetate hydrolase gene Fah, encoding the last enzyme in the tyrosine catabolic pathway. Lethal albino deletion c14CoS mice and mice with target-disrupted Fah are models for HT1, but they die in the perinatal period, albeit with a different phenotype from that seen in HT1 in humans. We first asked whether homozygous null mutation of the 4-hydroxyphenylpyruvate dioxygenase gene Hpd could rescue the homozygous c14CoS mice (c14CoS/c14CoS or Fah-/-). The double mutant Fah-/- Hpd-/- mice appeared normal, at least until age 18 months, and there was no evidence of liver disease, findings that facilitated examination of the effect of Fah-/- on mature and unmodified hepatocytes in vivo. The hepatocytes of Fah-/- undergo rapid apoptosis, and acute death follows. Essentially the same phenomena were observed when Fah-/- Hpd-/- mice were administered homogentisate intraperitoneally. These changes in liver pathology in Fah-/- Hpd-/- mice after the administration of homogentisate were associated with massive urinary excretion of succinylacetone. These results suggest that accumulation of fumarylacetoacetate, maleylacetoacetate, or succinylacetone seems to trigger the endogenous process of apoptosis in hepatocytes that lack fumarylacetoacetate hydrolase activity. This apoptosis may be related to the development of hepatocellular carcinomas seen in HT1 patients and pharmaceutically treated fumarylacetoacetate hydrolase-deficient mice.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1997

Familial lethal inheritance of a mutated paternal gene in females causing X-linked ornithine transcarbamylase (OTC) deficiency.

A Leu148Phe substitution of the ornithine transcarbamylase (OTC) gene was identified in a 2-year-old girl with OTC deficiency (14% of control). Her two elder sisters died in childhood of hyperammonemia, and the patient also died of OTC deficiency. Enzyme activity in Cos1 cells transfected by the mutant cDNA was undetectable, thereby indicating a definite pathogenic mutation. Familial gene analysis showed that the mother had wild-type OTC alleles on both X-chromosomes and the father was a mosaic for the mutant allele in his lymphocytes and spermatozoa. This clinical case shows that a somatic and germline mosaicism for a single-gene disorder led to an unusual pattern of X-linked inheritance in the family, and all three daughters in the family died of OTC deficiency. The possibility that inherited factors will lead to skewed X-inactivation needs to be considered.

Fatal Outcome↗
PubMed1997

In vivo correction with recombinant adenovirus of 4-hydroxyphenylpyruvic acid dioxygenase deficiencies in strain III mice.

Tyrosinemia type 3, caused by a genetic deficiency of 4-hydroxyphenylpyruvic acid dioxygenase (HPD) in tyrosine catabolism, is characterized by convulsion, ataxia, and mental retardation. The III mouse is a model of tyrosinemia type 3. HPD activity and protein are defective in the liver and its blood tyrosine levels are elevated, the range being between 1,100 and 1,656 microM. We constructed a recombinant adenoviral vector bearing the human HPD cDNA (AdexCAGhHPD), which is expressed under the control of a potent CAG promoter. III mice were injected with 1.0 x 10(8) to 1.0 x 10(9) pfu of AdexCAGhHPD through the tail vein. When 3.0 x 10(8) - 1.0 x 10(9) pfu were injected, blood tyrosine levels decreased within 3 hr, reached a normal range (under 300 microM), and remained at a low level for 2-6 weeks. Hepatic HPD activities also increased as early as 3 hr after the injection of 5.0 x 10(8) pfu, reached the levels comparable to the control mice in 3-7 days, and then decreased, and correlated well to blood tyrosine. Hepatic HPD expression was confirmed by Northern blot and immunoblot analyses. Histology revealed no difference (gross or microscopic) between the liver injected with AdexCAGhHPD and the control. No significant changes in blood tyrosine levels were noted after the second injection of 5.0 x 10(8) pfu of AdexCAGhHPD. Thus, the intravenous administration of the adenoviral vector bearing a foreign gene seems suitable for transient, early gene transfer into the liver.

4-Hydroxyphenylpyruvate Dioxygenase↗
PubMed1997

Amelioration of prolidase deficiency in fibroblasts using adenovirus mediated gene transfer.

Prolidase deficiency is an autosomal recessive inherited disease characterized clinically by frequent infections, mental retardation, and various skin lesions. Fundamental treatments for these manifestations have not been established. We performed adenovirus-mediated gene transfer of human prolidase cDNA into fibroblasts from patients with prolidase deficiency. Infection with the adenovirus vector carrying human prolidase cDNA increased prolidase activity in fibroblasts up to approximately 7.5 times of that of normal control fibroblasts. This indicates the feasibility of adenovirus-mediated gene therapy to treat patients with prolidase deficiency in the future.

Adenoviridae↗
PubMed1997

The effect of Bcg gene on antigen presentation of spleen adherent cells and peritoneal macrophages from Mycobacterium bovis BCG-infected Bcg(s) and Bcg(r) mice.

To determine the role of the Bcg gene in the resistance and susceptibility of BCG-infected C57BL/6 (Bcg(s)) and its Bcg(r) congenic mice, the antigen presenting ability of spleen adherent cells and peritoneal macrophages, delayed type hypersensitivity (DTH) and lymphocyte blastogenic responses were investigated. The results obtained indicate that the DTH and lymphocyte blastogenic responses in Bcg(r) congenic mice were higher than in the Bcg(s) mice. Stimulation of spleen adherent cells with live Mycobacterium bovis BCG or PPD-BCG resulted in a higher antigen presenting ability in Bcg(r) than in Bcg(s) mice. However, comparatively low responses were associated with M. avium stimulation, with those in Bcg(r) being higher than in Bcg(s). I-A expression was also comparatively higher in Bcg(r) than in Bcg(s) mice. This study demonstrates that the Bcg gene seems to exhibit some effect on the antigen presenting ability of macrophages in immune responses of the congenic mice.

Animals↗
PubMed1997

Mutations in the CLCN5 gene in Japanese patients with familial idiopathic low-molecular-weight proteinuria.

Familial idiopathic low-molecular-weight proteinuria (FILMWP) is a renal proximal tubulopathy that occurs predominantly in males. FILMWP is characterized by mild proteinuria consisting of low-molecular-weight proteinuria, aminoaciduria and relatively conserved renal function, but without rickets. To determine whether FILMWP is related to the CLCN5 gene, which is responsible for Dent's disease and two related disorders, we analyzed the CLCN5 gene from four Japanese families with FILMWP. We identified two novel mutations: one was a single base insertion at codon 520 serine in exon 10 and the other was a single base deletion at codon 403 tyrosine in exon 8. These mutations caused a shift in the reading frame, resulting in synthesis of truncated CLC5 proteins that lacked 220 (29%) and 314 (42%) amino acids, respectively. These mutations were demonstrated to cosegregate with the disease in two families, respectively. We conclude that the CLCN5 gene is responsible for this proximal renal tubulopathy in some Japanese families and that FILMWP is possibly a variant of Dent's disease.

Alleles↗
PubMed1997

Haplotype and mutation analysis in Japanese patients with Wilson disease.

Wilson disease (WD), an autosomal recessive disorder of copper transport, is characterized by impaired biliary excretion and by impaired incorporation of copper into ceruloplasmin. Toxic accumulation of copper causes tissue damage, primarily in the liver, brain, and kidneys. The gene for WD (ATP7B) has been cloned, and the protein product is predicted to be a copper-transporting P-type ATPase with high amino acid identity with that for Menkes disease, an X-linked disorder of copper transport. Mutation screening in WD patients has led to the identification of at least 40 mutations. In addition, haplotype analysis using three dinucleotide-repeat markers, D13S314, D13S301, and D13S316, has been a useful indicator of specific mutations. We have determined haplotypes for the patients and their parents and sibs, in 21 unrelated WD families from Japan. Twenty-eight different haplotypes were observed on 42 WD chromosomes. In all the patients, the ATP7B coding sequence, including the intron-exon boundaries, was screened for mutations, by SSCP, followed by direct-sequence analysis of the shifted fragments. We identified 13 mutations, of which 11 mutations are novel, including 7 mutations-1 insertion, 4 deletions, and 2 missense mutations-in the coding region. The mutations reported in previous studies are 2299insC and Arg778Leu. Two patients were shown to have the 2299insC mutation, which has occurred in many different haplotypes in several populations, indicating a mutation hot spot. Primer-extension analysis of ATP7B mRNA has revealed multiple transcription start sites. Four of the novel mutations (three 1-bp changes and one 5-bp deletion) occur in the 5' UTR and may result in altered expression of the WD gene.

Adenosine Triphosphatases↗
PubMed1997

Effects of Lentinus edodes, Grifola frondosa and Pleurotus ostreatus administration on cancer outbreak, and activities of macrophages and lymphocytes in mice treated with a carcinogen, N-butyl-N-butanolnitrosoamine.

ICR mice were treated with a carcinogen, N-butyl-N'-butanolnitrosoamine BBN), every day for 8 consecutive weeks and the effects of oral administration of edible mushrooms on the induction of urinary bladder carcinoma and on the activities of macrophages and lymphocytes were studied. Bladder carcinoma were found in all 10 mice (100%) treated with BBN alone, while we observed carcinoma only in 9 of 17 mice (52.9%), in 7 of 15 mice (46.7%) and 13 of 20 mice (65.0%) treated with Lentinus edodes, Grifola frondosa and Pleurotus ostreatus, respectively. Chemotactic activity of macrophages was suppressed in mice treated with BBN alone but maintained almost the normal level in mice treated with BBN plus Lentinus, Grifola or Pleurotus. Lymphocytes collected from mice treated with BBN plus each mushroom showed almost normal blastogenic response against concanavalin A, although those from mice treated with BBN alone completely retarded their response. Cytotoxic activity of lymphocytes against Yac-1 cells was also maintained at a normal level in mice treated with BBN plus each mushroom. Whereas in mice treated with BBN alone significant depression of NK cell activity occurred. Significantly higher cytotoxic activity against P-815 cells was observed in lymphocytes from mice treated with BBN plus each mushroom than that in lymphocytes from normal mice or mice treated with BBN alone.

Animals↗
PubMed1997

[Pitfall in 201Tl-99mTc subtraction scintigraphy: a case of 99mTc-pertechnetate uptake in a parathyroid hyperplasia].

201Tl-99mTc subtraction scintigraphy has been recognized as a useful procedure in the preoperative localization of hyperfunctioning parathyroid glands. We experienced a case which showed 99mTc-pertechnetate uptake in a parathyroid hyperplasia. This case warned us to focus a lot of attention on the detection for preoperative localization. There has been no such case reported in the previous Japanese literatures. Hypervascularity and thick fibrous capsule presumed explanation for a rare case of marked pertechnetate uptake into a parathyroid hyperplasia.

Adult↗
PubMed1996

Molecular cloning, tissue distribution, and chromosomal localization of human cationic amino acid transporter 2 (HCAT2).

Human cationic amino acid transporter 2 (HCAT2) was isolated from a human intestine cDNA library. The nucleotide sequence of the coding region predicts a 658-amino-acid protein with a calculated molecular weight of 71,669. As 91% of the residues are identical with those of the mouse cationic amino acid transporter 2 (MCAT2), HCAT2 seems to be a human counterpart of MCAT2. We found no isoform as was present in MCAT2. In Northern blot analysis, a single (9.0 kb) HCAT2 mRNA transcript was present in various human tissues. The highest level of expression was observed in skeletal muscle and the lowest level in the kidney. Hydropathy plots indicated that the translated protein is predicted to have 14 transmembrane domains with three potential N-glycosylation sites. Two patients with lysinuric protein intolerance (MIM No. 222700) were analyzed for HCAT2 cDNA but no mutation was detected. The HCAT2 gene was assigned to human chromosome 8p21.3-p22.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Prenatal monitoring in a family at high risk for ornithine transcarbamylase (OTC) deficiency: a new mutation of an A-to-C transversion in position +4 of intron 1 of the OTC gene that is likely to abolish enzyme activity.

DNA analysis of a male propositus with ornithine transcarbamylase (OTC) deficiency documented an A-to-C substitution in position +4 of intron 1. No other abnormalities were observed in the OTC gene, or at 563 bp upstream of the 5' site, which included a promoter region, or at 383 bp downstream of the termination codon, which included a polyadenylation signal sequence. This mutation produces an RsaI site in the sequence, which was used for prenatal monitoring in the fourth and fifth pregnancies. DNA from amniotic cells in the former case were positive for RsaI digestion and the SRY gene (sex determinant region Y), indicating hemizygosity for the mutant allele. OTC activity was not measurable, and mRNA of the OTC gene was not detected by Northern blotting in the affected fetal liver. RT-PCR (reverse transcription-PCR) demonstrated only the wild-type allele. Thus, the mutation interferes with RNA processing, and an extremely low amount of normally spliced mRNA for the OTC gene seems to have caused the disease in our patient. The fetus of the fifth pregnancy was a normal male, as confirmed postnatally.

Amino Acid Metabolism, Inborn Errors↗
PubMed1996

Correction of ornithine transcarbamylase deficiency in adult spf(ash) mice and in OTC-deficient human hepatocytes with recombinant adenoviruses bearing the CAG promoter.

Ornithine transcarbamylase (OTC) deficiency, the most common and severe inborn error of the urea cycle in humans, remains without adequate treatment, and mortality rates are high. Adenoviral vectors provide an efficient system for gene delivery, but there are problems, including toxicity. Efficient promoters that reduce the amount of vector required for treatment need to be developed. We constructed two recombinant adenoviral vectors, AdexCAGhOTC and AdexSR alpha hOTC, which harbor the human OTC gene under transcriptional control of CAG (a modified chicken beta-actin promoter with CMV-IE enhancer) and SR alpha (the SV40 early promoter with the R segment and part of the US segment of the HTLV-1 LTR), respectively. Each was tested in adult spf(ash) mice, an animal model of human OTC deficiency, and in primary human hepatocytes with OTC deficiency. Spf(ash) mice have a pronounced orotic aciduria as seen in humans. A complete recovery of hepatic OTC activity with minimal tissue damage was observed in these animals following the intravenous administration of AdexCAGhOTC alone. Western blot analysis confirmed hepatic OTC expression and normalization of orotic aciduria was evident for 60 days. Enzyme activities of primary human hepatocytes infected with AdexCAGhOTC were 10-40 times higher than those with AdexSR alpha hOTC. Thus, the adenoviral vector with an efficient promoter such as CAG, can be given further consideration for possible gene therapy in humans with OTC deficiency.

Actins↗
PubMed1996

Three brothers with progressive hepatic dysfunction and severe hepatic steatosis due to a patent ductus venosus.

Three Japanese brothers with progressive deterioration of hepatic function and fatty degeneration of the liver eventually leading to hepatic encephalopathy were recently encountered. Each of them had a congenital intrahepatic portosystemic venous shunt due to a patent ductus venosus. Liver dysfunction and hepatic steatosis reverted to normal with surgical correction of the ductus venosus. Our observations suggest that impairment of liver function occurs first in the presence of malnutrition related to a reduction of blood in the portal vein. Hepatic steatosis is a consequence of a depleted metabolism of hepatocytes. Congenital portosystemic venous shunt due to a patent ductus venosus in this family has a genetic background.

Angiography↗
PubMed1996

Phenotypic variability in male patients carrying the mutant ornithine transcarbamylase (OTC) allele, Arg40His, ranging from a child with an unfavourable prognosis to an asymptomatic older adult.

In five different Japanese families, we identified six male hemizygotes (aged 6, 9, 15, 17, 56, and 65 years) and a putative candidate (aged 48 years), carrying a mutant allele of the ornithine transcarbamylase (OTC) gene, a G to A substitution at nucleotide 119 in exon 2 generating histidine in place of arginine. OTC activity in the necropsied liver tissue was reduced to approximately 12% of the control and that of COS 1 cells transfected with Arg40His OTC cDNA was 10.2 +/- 1.8% of the control transfected with wild type OTC cDNA. Clinical features ranged from death during a hyperammonaemic attack (a 9 year old) to a 65 year old asymptomatic man. We consider that the amount of protein ingested by these subjects may be one predisposing factor leading to the manifestation of this disease.

Adolescent↗