A mouse model of familial porphyria cutanea tarda

Phillips, John D.; Jackson, Lindsey N.; Bunting, Michaeline; Franklin, Michael R.; Thomas, Kirk R.; Levy, Joanne E.; Andrews, Nancy C.; Kushner, James P.

doi:10.1073/pnas.98.1.259

Cited by 58 publications

(42 citation statements)

References 35 publications

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“…2,15 The conclusion that heterozygosity for mutant URO-D alleles is a risk factor for the development of PCT 15 is supported by the observation that heterozygous mice are more sensitive to porphyrinogenic stimuli than wild-type animals. 33 In heterozygous mice and humans displaying porphyric phenotypes, hepatic URO-D protein level is half-normal, but catalytic activity is reduced to approximately 20%. [33][34][35] This finding strongly suggests that an inhibitor of hepatic URO-D is generated when the porphyric phenotype becomes manifest.…”

Section: Mutations In Human Uro-d 3183mentioning

confidence: 99%

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Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase

Phillips

Parker

Schubert

et al. 2001

Blood

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Functional consequences of 12 mutations-10 missense, 1 splicing defect, and 1 frameshift mutation-were characterized in the uroporphyrinogen decarboxylase (URO-D) gene found in Utah pedigrees with familial porphyria cutanea tarda (F-PCT). All but one mutation altered a restriction site in the URO-D gene, permitting identification of affected relatives using a combination of polymerase chain reaction and restriction enzyme digestion. In a bacterial expression system, 3 of the missense mutants were found in inclusion bodies, but 7 were expressed as soluble proteins. Enzymatic activity of soluble, recombinant mutant URO-D genes ranged from 29% to 94% of normal. URO-D mRNA levels in Epstein-Barrvirus transformed cells derived from patients were normal (with the exception of the frameshift mutation) even though protein levels were lower than normal, suggesting that missense mutations generally cause unstable URO-Ds in vivo. The crystal structures of 3 mutant URO-Ds were solved, and the structural consequences of the mutations were defined. All missense mutations reported here and by others were mapped to the crystal structure of URO-D, and structural effects were predicted. These studies define structural and functional consequences of URO-D mutations occurring in patients with F-PCT. (Blood. 2001;98:3179-3185)

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Section: Mutations In Human Uro-d 3183mentioning

confidence: 99%

“…Homozygosity for URO-D null alleles is lethal, 33 but homozygosity or compound heterozygosity for mutant alleles that encode URO-D genes with some residual activity can be tolerated. 1,2 In homozygotes or compound heterozygotes, the porphyric phenotype is pronounced and is usually evident in early childhood.…”

Section: Mutations In Human Uro-d 3183mentioning

confidence: 99%

Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase

Phillips

Parker

Schubert

et al. 2001

Blood

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“…Mice treated with ALA were given drinking water supplemented with 2 mg/mL of δ-aminolevulinic acid (ALA; A3785; Sigma-Aldrich, Milano, Italy), as described previously (24).…”

Section: Milano Italy)mentioning

confidence: 99%

Crucial Role of FLVCR1a in the Maintenance of Intestinal Heme Homeostasis

Fiorito

Forni²,

Silengo

et al. 2015

Antioxidants & Redox Signaling

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“…The development of mouse models by gene knock-out technology is greatly facilitating our understanding of the pathogenic mechanisms and evaluation of novel treatments. [29][30][31] …”

Section: Treatment Of Acute Attacksmentioning

confidence: 99%

Porphyria for the general physician

Sarkany

2005

Clinical Medicine

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Awareness and consideration are essential in making/suspecting a diagnosis of the acute neuropsychiatric porphyriasAcute porphyria should be considered in the differential diagnosis of hyponatraemia, renal impairment and atypical psychiatric and neurologic disorders Accurate quantitation of porphobilinogen, δ-aminolaevulinate and porphyrins in laboratory samples is essential in confirming a diagnosis Recent developments in treatment and prevention strategies have considerably improved the quality of life of patients with porphyria Molecular genetics are not necessary in initial diagnosis, but are valuable in confirmatory investigations and in family studiesAccurate biochemical diagnosis is crucial in cutaneous porphyria since acute porphyrias (variegate porphyria and hereditary coproporphyria) can cause skin signs indistinguishable from a non-acute porphyria (porphyria cutanea tarda) Porphyria cutanea tarda often reflects underlying liver disease or haemochromatosis Neuropsychiatric featuresThe acute porphyrias are also known as the neuropsychiatric porphyrias due to the neurological and occasional psychiatric features of a severe acute attack. Occasionally, patients with a primarily psychiatric diagnosis are referred for consideration of an underlying porphyria. 7 Because of the stigma associated with a psychiatric diagnosis, patients and their relatives prefer a diagnosis of porphyria to one of a primary psychosis. A careful study by Patience et al 8 indicated that, with the exception of anxiety disorder, schizophrenia, bipolar disorder and simple depression are no more common in the acute porphyrias than in a control population. The basis of the association of chronic anxiety with porphyria is unclear. Some studies consider it secondary to recurrent acute attacks but it is equally common in fully latent cases. The symptoms may be quite disabling and referral for assessment and treatment (eg cognitive behavioural therapy) can be helpful.A recent report has highlighted the important relationship between epilepsy and the acute porphyrias. 9 Screening testsPrevious laboratory screening tests for porphyria were unreliable with false-positive and false-negative rates approaching 50%. 10 More recent semiquantitative tests are more accurate, but a definitive conclusion requires quantitative assay for porphobilinogen (PBG) and δ-aminolaevulinic acid (ALA) in an early morning urine sample. 11 Certain drugs may interfere with screening tests, while assays of PBG alone may be unreliable in aged urine samples, may not reflect the clinical activity of the porphyria, would not identify Doss porphyria (due to PBG synthase defect) and may miss cases of secondary porphyria (eg lead poisoning). Renal complicationsRenal complications of acute porphyria are recognised in the porphyria literature but nephrologists rarely consider them in the differential diagnosis of chronic renal disease. A recent update series on renal failure in this journal failed to mention porphyria. 12 Hypertension and analgesic nephropathy are not infrequ...

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A mouse model of familial porphyria cutanea tarda

Cited by 58 publications

References 35 publications

Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase

Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase

Crucial Role of FLVCR1a in the Maintenance of Intestinal Heme Homeostasis

Porphyria for the general physician

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