Congenital erythropoietic porphyria: Recent advances

Erwin, Angelika; Desnick, Robert J.

doi:10.1016/j.ymgme.2018.12.008

Cited by 53 publications

(82 citation statements)

References 86 publications

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“…Moreover, after allogeneic stem cell transplantation, the clinical findings disappeared and urine porphyrin levels returned to normal. Bone marrow transplantation has already been demonstrated to be effective in true CEP, although urinary porphyrins – even if considerably reduced – remained elevated owing to the sustained overproduction of hepatic porphyrins . Nevertheless, as in the case reported herein, bone marrow transplantation is a successful therapeutic approach for patients suffering from erythropoietic uroporphyria secondary to MDS as the origin of porphyrins is restricted to bone marrow.…”

Section: Discussionmentioning

confidence: 64%

“…This leads to the formation of nonphysiological isomer I porphyrin, which cannot be converted to haem and is accumulated in erythrocytes, inducing haemolysis. This porphyrin deposits in tissues, causing multisystemic disease and, as uroporphyrins are phototoxic, skin lesions appear in sun‐exposed areas . The diagnosis is suggested by markedly increased levels of urinary uroporphyrin I and coproporphyrin I isomers, and confirmed by the presence of biallelic UROS mutations or, exceptionally, by the identification of a homozygous mutation in the X‐linked gene GATA1 …”

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confidence: 99%

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Acquired erythropoietic uroporphyria secondary to myelodysplastic syndrome with chromosome 3 alterations: a case report

et al. 2018

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Congenital erythropoietic porphyria is a rare autosomal recessive disease caused by a deficiency of uroporphyrinogen III synthase, owing to mutations in UROS in chromosome 10. Occasionally, patients show a mild, late-onset disease, without germline UROS mutations, associated with haematological malignancies. We report a 65-year-old patient with photosensitivity, overexcretion of porphyrins and thrombocytopenia. Bone marrow analysis gave a diagnosis of myelodysplastic syndrome (MDS) with the presence of a derivative chromosome 3, possibly due to an inversion including 3q21 and 3q26 break points. After allogeneic stem-cell transplantation, complete remission of MDS and uroporphyria was achieved. To our knowledge, this is the first reported case of acquired erythropoietic uroporphyria associated with MDS, with chromosome 3 alterations.

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Section: Discussionmentioning

confidence: 64%

mentioning

confidence: 99%

Acquired erythropoietic uroporphyria secondary to myelodysplastic syndrome with chromosome 3 alterations: a case report

et al. 2018

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“…Congenital erythropoietic porphyria (CEP; OMIM #263700), is an ultra-rare autosomal recessive disease affecting 1:1,000,000 persons. CEP is caused by dysfunctions of the uroporphyrinogen III synthase (UROIIIS; EC 4.2.1.75), an enzyme involved in the heme biosynthetic pathway [ 110 , 111 ]. The lack of UROIIIS activity implies the accumulation of type I porphyrins which triggers in turn hemolysis, anemia, splenomegaly and severe phototoxic cutaneous lesions.…”

Section: Non-inhibitory Pharmacological Chaperones For Miscellaneomentioning

confidence: 99%

“…In most cases, CEP is due to UROS gene mutations which lead to unfolding, instability and rapid degradation of the mutated UROIIIS protein. Among these mutations (less than 50 according HGMD), the missense p.C73R is the most frequent one (about one-third of reported CEP cases) and the corresponding mutated proteins have an enzymatic stability <1% compared to the wild-type [ 110 ].…”

Section: Non-inhibitory Pharmacological Chaperones For Miscellaneomentioning

confidence: 99%

Second-Generation Pharmacological Chaperones: Beyond Inhibitors

et al. 2020

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Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins, such as enzymes, and a pathological loss-of-function may result from their early degradation. Since the proof of concept in the 2000s, the bioinspired pharmacological chaperone therapy became a relevant low-molecular-weight compound strategy against conformational diseases. The first-generation pharmacological chaperones were competitive inhibitors of mutant enzymes. Counterintuitively, in binding to the active site, these inhibitors stabilize the proper folding of the mutated protein and partially rescue its cellular function. The main limitation of the first-generation pharmacological chaperones lies in the balance between enzyme activity enhancement and inhibition. Recent research efforts were directed towards the development of promising second-generation pharmacological chaperones. These non-inhibitory ligands, targeting previously unknown binding pockets, limit the risk of adverse enzymatic inhibition. Their pharmacophore identification is however challenging and likely requires a massive screening-based approach. This review focuses on second-generation chaperones designed to restore the cellular activity of misfolded enzymes. It intends to highlight, for a selected set of rare inherited metabolic disorders, the strategies implemented to identify and develop these pharmacologically relevant small organic molecules as potential drug candidates.

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“…Congenital erythropoietic porphyria (CEP) is an autosomal recessive disorder caused by a profound deficiency in the enzymatic activity of uroporphyrinogen III synthase (UROS) (EC 4.2.1.75), the fourth enzyme of the heme biosynthetic pathway ( Erwin and Desnick, 2019 ; Ged et al., 2009 ; Richard et al., 2008 ). This defect leads to the accumulation of the fluorescent type I porphyrin isomers, causing dermatological lesions and hemolytic anemia.…”

Section: Introductionmentioning

confidence: 99%

Mutation-Specific Guide RNA for Compound Heterozygous Porphyria On-target Scarless Correction by CRISPR/Cas9 in Stem Cells

Prat

Toutain²,

Boutin

et al. 2020

Stem Cell Reports

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Summary CRISPR/Cas9 is a promising technology for gene correction. However, the edition is often biallelic, and uncontrolled small insertions and deletions (indels) concomitant to precise correction are created. Mutation-specific guide RNAs were recently tested to correct dominant inherited diseases, sparing the wild-type allele. We tested an original approach to correct compound heterozygous recessive mutations. We compared editing efficiency and genotoxicity by biallelic guide RNA versus mutant allele-specific guide RNA in iPSCs derived from a congenital erythropoietic porphyria patient carrying compound heterozygous mutations resulting in UROS gene invalidation. We obtained UROS function rescue and metabolic correction with both guides with the potential of use for porphyria clinical intervention. However, unlike the biallelic one, the mutant allele-specific guide was free of on-target collateral damage. We recommend this design to avoid genotoxicity and to obtain on-target scarless gene correction for recessive disease with frequent cases of compound heterozygous mutations.

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Congenital erythropoietic porphyria: Recent advances

Cited by 53 publications

References 86 publications

Acquired erythropoietic uroporphyria secondary to myelodysplastic syndrome with chromosome 3 alterations: a case report

Acquired erythropoietic uroporphyria secondary to myelodysplastic syndrome with chromosome 3 alterations: a case report

Second-Generation Pharmacological Chaperones: Beyond Inhibitors

Mutation-Specific Guide RNA for Compound Heterozygous Porphyria On-target Scarless Correction by CRISPR/Cas9 in Stem Cells

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