A nonsense mutation in the 4-hydroxyphenylpyruvic acid dioxygenase gene (Hpd) causes skipping of the constitutive exon and hypertyrosinemia in mouse strain III

Endo, Fumio; Awata, Hisataka; Katoh, Hideki; Matsuda, Ichiro

doi:10.1016/0888-7543(95)80122-3

Cited by 23 publications

(16 citation statements)

References 39 publications

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“…Genes and cDNAs encoding HPPDase have been identified from several mammalian, fungal, bacterial, and plant sources (Gershwin et al, 1987;Endo et al, 1992Endo et al, , 1995Hummel et al, 1992;Ruetschi et al, 1993;Coon et al, 1994;Denoya et al, 1994;Wilson et al, 1994;Wintermeyer et al, 1994;Kaneko et al, 1995;Wyckoff et al, 1995;Garcia et al, 1997) and show between 25% and 95% identity at the amino acid level. A computer search of the plant DNA databases, including 20,000 random Arabidopsis cDNAs (Newman et al, 1994), was conducted using human and bacterial HPPDase sequences as the query.…”

Section: Isolation and Characterization Of An Arabidopsis Hppdase Cdnamentioning

confidence: 99%

Complementation of the Arabidopsispds1Mutation with the Gene Encodingp-Hydroxyphenylpyruvate Dioxygenase

1998

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Plastoquinone and tocopherols are the two major quinone compounds in higher plant chloroplasts and are synthesized by a common pathway. In previous studies we characterized two loci in Arabidopsis defining key steps of this biosynthetic pathway. Mutation of the PDS1 locus disrupts the activity of p-hydroxyphenylpyruvate dioxygenase (HPPDase), the first committed step in the synthesis of both plastoquinone and tocopherols in plants. Although plants homozygous for the pds1 mutation could be rescued by growth in the presence of homogentisic acid, the product of HPPDase, we were unable to determine if the mutation directly or indirectly disrupted HPPDase activity. This paper reports the isolation of a cDNA, pHPPD, encoding Arabidopsis HPPDase and its functional characterization by expression in both plants and Escherichia coli. pHPPD encodes a 50-kD polypeptide with homology to previously identified HPPDases, including 37 highly conserved amino acid residues clustered in the carboxyl region of the protein. Expression of pHPPD in E. coli catalyzes the accumulation of homogentisic acid, indicating that it encodes a functional HPPDase enzyme. Mapping of pHPPD and co-segregation analysis of the pds1 mutation and the HPPD gene indicate tight linkage. Constitutive expression of pHPPD in a pds1 mutant background complements this mutation. Finally, comparison of the HPPD genomic sequences from wild type and pds1 identified a 17-bp deletion in the pds1 allele that results in deletion of the carboxyterminal 26 amino acids of the HPPDase protein. Together, these data conclusively demonstrate that pds1 is a mutation in the HPPDase structural gene.

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Section: Isolation and Characterization Of An Arabidopsis Hppdase Cdnamentioning

confidence: 99%

Complementation of the Arabidopsispds1Mutation with the Gene Encodingp-Hydroxyphenylpyruvate Dioxygenase

1998

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“…HppD has been described in humans (4,44), mouse (9), and rat (10), as well as plants (14,16), fungi (63), and prokaryotes (8,45). There is considerable interest in the HGA catabolic pathway, because HppD in plants is an important herbicide target (5,15,23) and many severe human diseases, like phenylketonuria (18); alkaptonuria (52); tyrosinemias I, II, and III; and hawkinsinuria (48), are associated with enzyme deficiencies in the catabolism of tyrosine.…”

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Burkholderia cenocepacia C5424 Produces a Pigment with Antioxidant Properties Using a Homogentisate Intermediate

Keith¹,

Killip²,

et al. 2007

J Bacteriol

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Burkholderia cenocepacia is a gram-negative opportunistic pathogen that belongs to the Burkholderia cepacia complex. B. cenocepacia can survive intracellularly within phagocytic cells, and some epidemic strains produce a brown melanin-like pigment that can scavenge free radicals, resulting in the attenuation of the host cell oxidative burst. In this work, we demonstrate that the brown pigment produced by B. cenocepacia C5424 is synthesized from a homogentisate (HGA) precursor. The disruption of BCAL0207 (hppD) by insertional inactivation resulted in loss of pigmentation. Steady-state kinetic analysis of the BCAL0207 gene product demonstrated that it has 4-hydroxyphenylpyruvic acid dioxygenase (HppD) activity. Pigmentation could be restored by complementation providing hppD in trans. The hppD mutant was resistant to paraquat challenge but sensitive to H 2 O 2 and to extracellularly generated superoxide anions. Infection experiments in RAW 264.7 murine macrophages showed that the nonpigmented bacteria colocalized in a dextran-positive vacuole, suggesting that they are being trafficked to the lysosome. In contrast, the wild-type strain did not localize with dextran. Colocalization of the nonpigmented strain with dextran was reduced in the presence of the NADPH oxidase inhibitor diphenyleneiodonium, and also the inducible nitric oxide inhibitor aminoguanidine. Together, these observations suggest that the brown pigment produced by B. cenocepacia C5424 is a pyomelanin synthesized from an HGA intermediate that is capable of protecting the organism from in vitro and in vivo sources of oxidative stress.

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“…In tiie present study, we developed an experimental model of gene tiierapy for defective ketoacid metaboUsm of tyrosine in hepatocytes (Endo et al, , 1995. hi our ongoing related smdies, we find that recombinant adenovirus with a CAG promoter (modified chicken j8-actin promoter witfi CMV-IE enhancer) (Miyazaki et al, 1989;Niwa et al, 1991) is effective for expressing a foreign gene in Uvers of mice (Kiwaki et al, 1996).…”

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confidence: 91%

“…Mouse sttain /// is a model for human tyrosinemia type 3 and is characterized by mild elevation of blood tyrosine and ttie absence of visceral injuries . There is a C-to-T ttansition at -1-7 nucleotide on exon 7 of ttie HPD gene on chromosome 5 of the /// mouse, resulting in the premature termination of ttanslation (Endo et al, 1995). Using tins mouse model, expression of the functional HPD gene in hepatocytes is expected to normalize blood tyrosine levels.…”

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confidence: 98%

In VivoCorrection with Recombinant Adenovirus of 4-Hydroxyphenylpyruvic Acid Dioxygenase Deficiencies in StrainIIIMice

Kubo¹,

Kiwaki²,

Awata³

et al. 1997

Human Gene Therapy

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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.

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A nonsense mutation in the 4-hydroxyphenylpyruvic acid dioxygenase gene (Hpd) causes skipping of the constitutive exon and hypertyrosinemia in mouse strain III

Cited by 23 publications

References 39 publications

Complementation of the Arabidopsispds1Mutation with the Gene Encodingp-Hydroxyphenylpyruvate Dioxygenase

Complementation of the Arabidopsispds1Mutation with the Gene Encodingp-Hydroxyphenylpyruvate Dioxygenase

Burkholderia cenocepacia C5424 Produces a Pigment with Antioxidant Properties Using a Homogentisate Intermediate

In VivoCorrection with Recombinant Adenovirus of 4-Hydroxyphenylpyruvic Acid Dioxygenase Deficiencies in StrainIIIMice

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