Murine models of the human porphyrias: Contributions toward understanding disease pathogenesis and the development of new therapies

Publication date: Available online 18 January 2019Source: Molecular Genetics and MetabolismAuthor(s): Makiko Yasuda, Robert J. DesnickAbstractMouse models of the human porphyrias have proven useful for investigations of disease pathogenesis and to facilitate the development of new therapeutic approaches. To date, mouse models have been generated for all major porphyrias, with the exception of X-linked protoporphyria (XLP) and the ultra rare 5-aminolevulinic acid dehydratase deficient porphyria (ADP). Mouse models have been generated for the three autosomal dominant acute hepatic porphyrias, acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). The AIP mice, in particular, provide a useful investigative model as they have been shown to have acute biochemical attacks when induced with the prototypic porphyrinogenic drug, phenobarbital. In addition to providing important insights into the disease pathogenesis of the neurological impairment in AIP, these mice have been valuable for preclinical evaluation of liver-targeted gene therapy and RNAi-mediated approaches. Mice with severe HMBS deficiency, which clinically and biochemically mimic the early-onset homozygous dominant AIP (HD-AIP) patients, have been generated and were used to elucidate the striking phenotypic differences between AIP and HD-AIP. Mice modeling the hepatocutaneous porphyria, porphyria cutanea tarda (PCT), made possible the identification of the iron-dependent inhibi...
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research

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Publication date: Available online 31 July 2019Source: Molecular Genetics and MetabolismAuthor(s): Charles J. Parker, Robert J. Desnick, Montgomery D. Bissel, Joseph R. Bloomer, Ashwani Singal, Laurent Gouya, Herve Puy, Karl E. Anderson, Manisha Balwani, John D. PhillipsAbstractErythropoietic protoporphyria (EPP), the most common porphyria of childhood and the third most common porphyria of adulthood, is characterized clinically by painful, non-blistering cutaneous photosensitivity. Two distinct inheritance patterns involving mutations affecting genes that encode enzymes of the heme biosynthetic pathway underlie the clinic...
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research
Publication date: Available online 22 April 2019Source: Molecular Genetics and MetabolismAuthor(s): John D. PhillipsAbstractPorphyrias, is a general term for a group of metabolic diseases that are genetic in nature. In each specific porphyria the activity of specific enzymes in the heme biosynthetic pathway is defective and leads to accumulation of pathway intermediates. Phenotypically, each disease leads to either neurologic and/or photocutaneous symptoms based on the metabolic intermediate that accumulates. In each porphyria the distinct patterns of these substances in plasma, erythrocytes, urine and feces are the basis ...
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research
Erica S. Tarabadkar† and Michi M. Shinohara*† Division of Dermatology, University of Washington, Seattle, WA, United States Skin directed therapies (SDTs) serve important roles in the treatment of early stage cutaneous T-cell lymphoma (CTCL)/mycosis fungoides (MF), as well as managing symptoms and improving quality of life of all stages. There are now numerous options for topical therapies that demonstrate high response rates, particularly in early/limited MF. Phototherapy retains an important role in treating MF, with increasing data supporting efficacy and long-term safety of both UVB and PUVA as ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Publication date: June 2019Source: Molecular Genetics and Metabolism Reports, Volume 19Author(s): A. Moghe, V.M.S. Ramanujam, J.D. Phillips, R.J. Desnick, K.E. AndersonAbstractA 78-year-old man with a history of neonatal anemia and jaundice and life-long photosensitivity was found to have harderoporphyria, as evidenced by increased porphyrins in urine, plasma, erythrocytes and feces including large amounts of harderoporphyrin in feces and erythrocytes. Two previously undescribed coproporphyrinogen oxidase (CPOX) mutations were identified, including a deletion of four amino acids in a region of the enzyme mutated in 7 of th...
Source: Molecular Genetics and Metabolism Reports - Category: Genetics & Stem Cells Source Type: research
Publication date: Available online 23 January 2019Source: Molecular Genetics and MetabolismAuthor(s): Katell Peoc'h, Gael Nicolas, Caroline Schmitt, Arienne Mirmiran, Raed Daher, Thibaud Lefèbvre, Laurent Gouya, Zoubida Karim, Hervé PuyAbstractRecently, new genes and molecular mechanisms have been identified in patients with porphyrias and sideroblastic anemias (SA). They all modulate either directly or indirectly the δ-aminolevulinic acid synthase (ALAS) activity. ALAS, is encoded by two genes: the erythroid-specific (ALAS2), and the ubiquitously expressed (ALAS1). In the liver, ALAS1 controls the rate...
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research
Publication date: Available online 18 January 2019Source: Molecular Genetics and MetabolismAuthor(s): Makiko Yasuda, Robert J. DesnickAbstractMouse models of the human porphyrias have proven useful for investigations of disease pathogenesis and to facilitate the development of new therapeutic approaches. To date, mouse models have been generated for the major porphyrias, with the exception of X-linked protoporphyria (XLP) and the ultra rare 5-aminolevulinic acid dehydratase deficiency porphyria (ADP). Mouse models have been generated for all three autosomal dominant acute hepatic porphyrias, acute intermittent porphyria (A...
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research
Publication date: Available online 27 December 2018Source: Molecular Genetics and MetabolismAuthor(s): Angelika L. Erwin, Robert J. DesnickAbstractCongenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder characterized by photosensitivity and by hematologic abnormalities in affected individuals. CEP is caused by mutations in the uroporphyrinogen synthase (UROS) gene. In three reported cases, CEP has been associated with a specific X-linked GATA1 mutation. Disease-causing mutations in either gene result in absent or markedly reduced UROS enzymatic activity. This in turn leads to the accumulation of th...
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research
Rationale: Acute intermittent porphyria (AIP) is caused by hydroxymethylbilane synthase (HMBS) gene mutation. Patient concerns: A Chinese female patient with very typical AIP symptoms of severe abdominal pain, seizures, hypertension, and tachycardia, accompanied with hyponatremia, anemia, and hyperbilirubinemia. Diagnoses: She was diagnosed as AIP based on positive result of urine porphobilinogen and her clinical syndrome. Interventions: The proband was treated with intravenous glucose (at least 250 g per day) for 4 days. HMBS mutation was investigated in this family by Sanger sequencing. Outcomes: A hetero...
Source: Medicine - Category: Internal Medicine Tags: Research Article: Clinical Case Report Source Type: research
CONCLUSION: In our opinion, SPET/CT could have a key role in this setting of patients due to its high sensitivity and reliability in mild-to-moderate brain perfusion defects detection. Moreover, the quantitative analysis by using neurostat may allow to recognize even mild brain perfusion alterations, difficult to detect only visually. PMID: 29705816 [PubMed - in process]
Source: Hellenic Journal of Nuclear Medicine - Category: Nuclear Medicine Tags: Hell J Nucl Med Source Type: research
Yongjiang Zheng, Jiehua Xu, Shengran Liang, Dongjun Lin, Santasree Banerjee
Source: Frontiers in Genetics - Category: Genetics & Stem Cells Source Type: research
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