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Nucleic Acids Research Nov 2021CSA and CSB proteins are key players in transcription-coupled nucleotide excision repair (TC-NER) pathway that removes UV-induced DNA lesions from the transcribed...
CSA and CSB proteins are key players in transcription-coupled nucleotide excision repair (TC-NER) pathway that removes UV-induced DNA lesions from the transcribed strands of expressed genes. Additionally, CS proteins play relevant but still elusive roles in other cellular pathways whose alteration may explain neurodegeneration and progeroid features in Cockayne syndrome (CS). Here we identify a CS-containing chromatin-associated protein complex that modulates rRNA transcription. Besides RNA polymerase I (RNAP1) and specific ribosomal proteins (RPs), the complex includes ferrochelatase (FECH), a well-known mitochondrial enzyme whose deficiency causes erythropoietic protoporphyria (EPP). Impairment of either CSA or FECH functionality leads to reduced RNAP1 occupancy on rDNA promoter that is associated to reduced 47S pre-rRNA transcription. In addition, reduced FECH expression leads to an abnormal accumulation of 18S rRNA that in primary dermal fibroblasts from CS and EPP patients results in opposed rRNA amounts. After cell irradiation with UV light, CSA triggers the dissociation of the CSA-FECH-CSB-RNAP1-RPs complex from the chromatin while it stabilizes its binding to FECH. Besides disclosing a function for FECH within nucleoli, this study sheds light on the still unknown mechanisms through which CSA modulates rRNA transcription.
Topics: Cell Line, Transformed; Cell Survival; Chromatin Immunoprecipitation; Cockayne Syndrome; DNA Damage; DNA Helicases; DNA Repair; DNA Repair Enzymes; Ferrochelatase; Fibroblasts; Gene Expression Regulation; Humans; Poly-ADP-Ribose Binding Proteins; RNA Polymerase I; RNA, Ribosomal; Ribosomal Proteins; Transcription Factors; Transcription, Genetic; Ultraviolet Rays
PubMed: 34581821
DOI: 10.1093/nar/gkab819 -
Digestive and Liver Disease : Official... Apr 2022In erythropoietic protoporphyria (EPP), which presents with severe painful phototoxicity, progressive deposition of protoporphyrins in hepatocytes and bile canaliculi...
BACKGROUND
In erythropoietic protoporphyria (EPP), which presents with severe painful phototoxicity, progressive deposition of protoporphyrins in hepatocytes and bile canaliculi may result in liver disease. Clinically EPP related liver disease ranges from mildly elevated liver enzymes to cirrhosis and acute cholestatic hepatic failure. The prevalence of liver disease in EPP, and factors predicting the risk of developing liver disease, have not been defined in a large series of unselected EPP patients.
AIM
To determine the prevalence of liver disease in EPP-patients.
METHODS
A single-center prospective unselected cohort study of 114 adult EPP patients, who underwent routine laboratory testing, abdominal ultrasonography and transient elastography to assess the presence of steatosis (controlled attenuation parameter,dB/m) and liver stiffness (kPa).
RESULTS
114 adult EPP patients were included. Elevated liver enzymes were found in 6.2% of the patients. Liver steatosis was detected in 29.0%, and significant fibrosis as assessed with liver stiffness measurements was present in 9.6% of patients. BMI positively predicted CAP-values (p = 0.026); and protoporphyrin IX levels (p = 0.043) positively predicted liver stiffness.
CONCLUSIONS
This study demonstrates a prevalence of hepatic steatosis and fibrosis in adult EPP-patients comparable to that found in the general population. Protoporphyrin IX levels correlate with increased liver stiffness in EPP.
Topics: Adult; Cohort Studies; Humans; Liver; Liver Diseases; Prospective Studies; Protoporphyria, Erythropoietic
PubMed: 34475006
DOI: 10.1016/j.dld.2021.08.007 -
Photodermatology, Photoimmunology &... Mar 2022Erythropoietic protoporphyria (EPP) is a rare disorder of heme biosynthesis hallmarked by early-onset photosensitivity and mainly due to defective ferrochelatase...
Ultraviolet A phototest positivity is associated with higher free erythrocyte protoporphyrin IX concentration and lower transferrin saturation values in erythropoietic protoporphyria.
BACKGROUND
Erythropoietic protoporphyria (EPP) is a rare disorder of heme biosynthesis hallmarked by early-onset photosensitivity and mainly due to defective ferrochelatase activity leading to increased erythrocyte protoporphyrin IX (PPIX) levels. Evidence regarding the relationship between erythrocyte PPIX concentration and photosensitivity is limited.
METHODS
To investigate the relationship between free erythrocyte PPIX (FEP) concentration; routine laboratory tests, particularly iron metabolism biomarkers; and ultraviolet (UV) A/visible light phototesting findings, 20 genetically confirmed EPP and one XLPP treatment-naive patients were included in our study. They underwent UVA and visible light phototesting. On the same day, blood samples were collected for measurement of FEP, serum iron, transferrin, transferrin saturation, and ferritin, 25-hydroxyvitamin D, and liver enzyme levels.
RESULTS
Median FEP concentration at the time of phototesting was 57.50 (IQR: 34.58-102.70) μg/g of Hb. UVA and visible light phototesting were positive in 9 (42.9%) and 8 (38.1%) patients, respectively. Median FEP concentration was significantly higher in UVA phototest-positive patients than in those negative (64.37 [IQR: 57.45-121.82] vs 45.35 [IQR: 24.53-74.61] μg/g of Hb, respectively; P = .04486). Similarly, UVA photosensitive individuals had significantly lower median serum iron levels (61.5 [IQR: 33.5-84] μg/dL vs 109 [IQR: 63.25-154] μg/dL, respectively; P = .01862) and transferrin saturation values (15.005 [IQR: 7.0775-18.41] % vs 29.645 [IQR: 17.8225-34.3575] %; P = .0109) than those negative.
CONCLUSIONS
Our study demonstrates that UVA phototest positivity is associated with higher FEP concentration and lower transferrin saturation and serum iron concentration in EPP.
Topics: Erythrocytes; Humans; Protoporphyria, Erythropoietic; Protoporphyrins; Transferrins
PubMed: 34420239
DOI: 10.1111/phpp.12727 -
Journal of Patient-reported Outcomes Aug 2021
PubMed: 34396462
DOI: 10.1186/s41687-021-00348-4 -
Journal of Patient-reported Outcomes Aug 2021A novel treatment has been developed for erythropoietic protoporphyria (EPP) (a rare condition that leaves patients highly sensitive to light). To fully understand the...
BACKGROUND
A novel treatment has been developed for erythropoietic protoporphyria (EPP) (a rare condition that leaves patients highly sensitive to light). To fully understand the burden of EPP and the benefit of treatment, a novel patient reported outcome (PRO) measure was developed called the EPP-QoL. This report describes work to support the validation of this measure.
METHODS
Secondary analysis of trial data was undertaken. These analyses explored the underlying factor structure of the measure. This supported the deletion of some items. Further work then explored the reliability of these factors, their construct validity and estimates of meaningful change.
RESULTS
The factor analyses indicated that the items could be summarised in terms of two factors. One of these was labelled EPP Symptoms and the other EPP Wellbeing, based on the items included in the domain. EPP Symptoms had evidence to support its reliability and validity. EPP Wellbeing had poor psychometric properties.
CONCLUSIONS
Based on the analysis it was recommended to drop the EPP Wellbeing domain (and associated items). EPP Symptoms, despite limitations in the development of items, showed evidence of validity. This work is consistent with the recommendations of a task force that provided recommendations regarding the development, modification and use of PROs in rare diseases.
PubMed: 34342778
DOI: 10.1186/s41687-021-00345-7 -
Der Internist Sep 2021Porphyrias are caused by enzyme defects along the heme biosynthetic pathway. The first line diagnosis of porphyria is based on specific biochemical patterns of elevated...
Porphyrias are caused by enzyme defects along the heme biosynthetic pathway. The first line diagnosis of porphyria is based on specific biochemical patterns of elevated porphyrins and porphyrin precursors in urine, feces, and blood. In clinically active disease accumulated porphyrin precursors and/or porphyrins lead to abdominal, neurologic, psychiatric, endocrine and cardiovascular symptoms, liver damage and/or skin photosensitivity. Porphyrias are classified into acute and nonacute forms. Patients with symptomatic (clinically active) acute hepatic porphyria, e.g. acute intermittent porphyria, porphyria variegata, hereditary coproporphyria, and aminolevulinic acid dehydratase deficiency porphyria, display accumulation of porphyrin precursors, 5‑aminolevulinic acid and porphobilinogen due to regulation disorder. In the non-acute forms of porphyria, such as porphyria cutanea tarda, erythropoietic porphyria, X‑linked protoporphyria and congenital erythropoietic porphyria, accumulated porphyrins lead to skin photosensitivity and occasionally also to severe liver damage. Several different options for treatment, proven and innovative ones, are available for most porphyrias.
Topics: Humans; Porphyria Cutanea Tarda; Porphyria, Acute Intermittent; Porphyrias; Porphyrias, Hepatic; Porphyrins
PubMed: 34185109
DOI: 10.1007/s00108-021-01066-1 -
Cytotherapy Nov 2021The outbreak of coronavirus disease 2019 (COVID-19) has disproportionately affected patients with comorbidities, including recipients of solid organ and hematopoietic...
The outbreak of coronavirus disease 2019 (COVID-19) has disproportionately affected patients with comorbidities, including recipients of solid organ and hematopoietic stem cell transplants (SCT). Upon recovery from COVID-19, the degree of the immunological protection from reinfection remains unclear. Here we describe a 33-year-old patient with erythropoietic protoporphyria (EPP) who had undergone liver transplantation with splenectomy followed by allogeneic SCT in 2013 after an initial failed liver and umbilical cord transplant. The patient developed mild upper respiratory symptoms in the spring of 2020 and was found to have anti-SARS-CoV2 antibodies suggesting past infection. A comprehensive analysis of T cell functionality in peripheral blood from this patient revealed robust in vitro responses against SARS CoV2 antigens Spike (S) 1 and 2, membrane (M) and nucleoprotein (NP), comparable to the reactivity against common antigens from CMV, EBV, Ad and BK viruses, while only low reactivity was seen in healthy donors without documented history of COVID-19. Moreover, the patient displayed a marked recognition of counterpart antigens from related human coronaviruses (hCoVs) 229E, OC43, NL63 and HKU1. Thus, despite lifelong immunosuppression, this survivor of COVID-19 retained a remarkable degree of immunocompetence and showed broad-spectrum T cell memory specific for SARS-CoV2 and related hCoVs including less studied hCoV M and NP antigens. The study highlights the role of cellular immunity after natural COVID-19 infection, suggesting broader use of T cell assays as a tool for risk stratification, measurement of immunocompetence and/or post-infection or post-vaccination protection, and possible T cell-based adoptive immunotherapy strategies in high-risk patients.
Topics: Adult; Antibodies, Viral; COVID-19; Coronavirus OC43, Human; Hematopoietic Stem Cell Transplantation; Humans; Liver; RNA, Viral; SARS-CoV-2; T-Lymphocytes
PubMed: 34183244
DOI: 10.1016/j.jcyt.2021.05.005 -
Genetics in Medicine : Official Journal... Sep 2021Patients with erythropoietic protoporphyria (EPP), a severe painful photodermatosis, experience prodromal sensations when exposed to sunlight, which are the "warning...
PURPOSE
Patients with erythropoietic protoporphyria (EPP), a severe painful photodermatosis, experience prodromal sensations when exposed to sunlight, which are the "warning signals" to exit the sun, as prolonged exposure causes an excruciatingly painful phototoxic attack. The unique prodromal cutaneous sensations are reversible and differ from the severe burning pain attack lasting 2-7 days. Previously, afamelanotide treatment was studied using time to pain or time outside as primary outcome measures. Since patients have an ingrained fear of sunlight, these measures did not capture the full treatment effect. We retrospectively characterized and evaluated time to prodrome (TTP) as a safer, patient-reported outcome (PRO) measure in afamelanotide-treated patients.
METHODS
Structured interviews recorded TTP before and during afamelanotide treatment in retrospective US and Dutch cohort studies.
RESULTS
Thirty-one US and 58 Dutch EPP patients participated. Before afamelanotide treatment, 54.8% US and 39.7% Dutch patients reported TTP onset <10 minutes in direct sunlight. In both studies, patients' TTP's were significantly longer during afamelanotide treatment (p < 0.0001). All US patients' TTP increased; no TTP was <10 minutes. Among Dutch patients 81% improved; only 10.3% reported TTPs < 10 minutes.
CONCLUSION
EPP patients reported substantial improvements in TTP during afamelanotide treatment. TTP could provide a safer, PRO-based efficacy endpoint for assessing future EPP treatments.
Topics: Humans; Pain; Patient Reported Outcome Measures; Protoporphyria, Erythropoietic; Retrospective Studies; Sunlight
PubMed: 33941881
DOI: 10.1038/s41436-021-01176-z -
Cell Chemical Biology Aug 2021Erythropoietic protoporphyria (EPP) is a rare disease in which patients experience severe light sensitivity. It is caused by a deficiency of ferrochelatase (FECH), the...
Erythropoietic protoporphyria (EPP) is a rare disease in which patients experience severe light sensitivity. It is caused by a deficiency of ferrochelatase (FECH), the last enzyme in heme biosynthesis (HBS). The lack of FECH causes accumulation of its photoreactive substrate protoporphyrin IX (PPIX) in patients' erythrocytes. Here, we explored an approach for the treatment of EPP by decreasing PPIX synthesis using small-molecule inhibitors directed to factors in the HBS pathway. We generated a FECH-knockout clone from K562 erythroleukemia cells, which accumulates PPIX and undergoes oxidative stress upon light exposure. We used these matched cell lines to screen a set of publicly available inhibitors of factors in the HBS pathway. Inhibitors of the glycine transporters GlyT1 and GlyT2 lowered levels of PPIX and markers of oxidative stress selectively in K562 cells, and in primary erythroid cultures from an EPP patient. Our findings open the door to investigation of glycine transport inhibitors for HBS disorders.
Topics: Cells, Cultured; Erythrocytes; Glycine Plasma Membrane Transport Proteins; Humans; K562 Cells; Molecular Structure; Protoporphyria, Erythropoietic; Protoporphyrins
PubMed: 33756123
DOI: 10.1016/j.chembiol.2021.02.021 -
Frontiers in Immunology 2021The homeostasis of tissues in a chronic disease is an essential function of the alternative pathway (AP) of the complement system (CS). However, if not controlled, it...
The homeostasis of tissues in a chronic disease is an essential function of the alternative pathway (AP) of the complement system (CS). However, if not controlled, it may also be detrimental to healthy cells with a consequent aggravation of symptoms. The protoporphyria (PP) is a rare chronic disease that causes phototoxicity in visible light with local skin pain and general malaise. In order to establish if there is a systemic involvement of the CS during sun exposure, we designed a non-invasive method with a serum collection in winter and summer from 19 PP and 13 controls to detect the levels of CS protein: Properdin, Factor H (FH), and C5. Moreover, the global radiation data were collected from the regional agency of environmental protection (ARPA). The results show growing values for every protein in patients with PP, compared to control, in both seasons, in particular in summer compared to winter. To reinforce the evidence, we have estimated the personal exposure of patients based on the global radiation data. The main factors of the AP increased over the season, confirming the involvement of the AP in relation to light exposure. The systemic response could justify the general malaise of patients after long light exposure and can be exploited to elucidate new therapeutic approaches.
Topics: Adult; Biomarkers; Complement C5; Complement Factor H; Complement Pathway, Alternative; Complement System Proteins; Disease Susceptibility; Female; Humans; Male; Middle Aged; Properdin; Protoporphyria, Erythropoietic; Seasons; Sunlight
PubMed: 33664746
DOI: 10.3389/fimmu.2021.615620