Hypermethylation of the wild-type ferrochelatase allele is closely associated with severe liver complication in a family with erythropoietic protoporphyria

Hepatocellular carcinomas (HCCs) mainly develop from liver cirrhosis and severe liver fibrosis that are established with long-lasting inflammation of the liver. Silencing of the suppressor of the cytokine signaling-1 (SOCS1) gene, a negative regulator of cytokine signaling, by DNA methylation has been implicated in development or progress of HCC. However, how SOCS1 contributes to HCC is unknown. We examined SOCS1 gene methylation in >200 patients with chronic liver disease and found that the severity of liver fibrosis is strongly correlated with SOCS1 gene methylation. In murine liver fibrosis models using dimethylnitrosamine, mice with haploinsufficiency of the SOCS1 gene (SOCS1−/+ mice) developed more severe liver fibrosis than did wild-type littermates (SOCS1+/+ mice). Moreover, carcinogen-induced HCC development was also enhanced by heterozygous deletion of the SOCS1 gene. These findings suggest that SOCS1 contributes to protection against hepatic injury and fibrosis, and may also protect against hepatocarcinogenesis.

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Inheritance in Erythropoietic Protoporphyria: A Common Wild-Type Ferrochelatase Allelic Variant With Low Expression Accounts for Clinical Manifestation

Blood ◽

10.1182/blood.v93.6.2105.406k28_2105_2110 ◽

1999 ◽

Vol 93 (6) ◽

pp. 2105-2110 ◽

Cited By ~ 97

Author(s):

Laurent Gouya ◽

Herve Puy ◽

Jerôme Lamoril ◽

Vasco Da Silva ◽

Bernard Grandchamp ◽

...

Keyword(s):

Autosomal Dominant ◽

Absolute Risk ◽

Clinical Manifestations ◽

Allelic Variant ◽

Control Group ◽

Wild Type ◽

Clinical Expression ◽

Erythropoietic Protoporphyria ◽

Autosomal Dominant Disorder ◽

Low Expression

Erythropoietic protoporphyria (EPP) is a rare autosomal dominant disorder of heme biosynthesis characterized by partial decrease in ferrochelatase (FECH; EC 4.99.1.1) activity with protoporphyrin overproduction and consequent painful skin photosensitivity and rarely liver disease. EPP is normally inherited in an autosomal dominant pattern with low clinical penetrance; the many different mutations that have been identified are restricted to one FECH allele, with the other one being free of any mutations. However, clinical manifestations of dominant EPP cannot be simply a matter ofFECH haploinsufficiency, because patients have enzyme levels that are lower than the expected 50%. From RNA analysis in one family with dominant EPP, we recently suggested that clinical expression required coinheritance of a normal FECH allele with low expression and a mutant FECH allele. We now show that (1) coinheritance of a FECH gene defect and a wild-type low-expressed allele is generally involved in the clinical expression of EPP; (2) the low-expressed allelic variant was strongly associated with a partial 5′ haplotype [−251G IVS1−23T IVS2μsatA9] that may be ancestral and was present in an estimated 10% of a control group of Caucasian origin; and (3) haplotyping allows the absolute risk of developing the disease to be predicted for those inheriting FECH EPP mutations. EPP may thus be considered as an inherited disorder that does not strictly follow recessive or dominant rules. It may represent a model for phenotype modulation by mild variation in expression of the wild-type allele in autosomal dominant diseases.

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Letter to the editor: Diagnosis of erythropoietic protoporphyria with severe liver injury - a case report

World Journal of Gastroenterology ◽

10.3748/wjg.v25.i30.4292 ◽

2019 ◽

Vol 25 (30) ◽

pp. 4292-4293

Author(s):

Debby Wensink ◽

Margreet AEM Wagenmakers ◽

JH Paul Wilson ◽

Janneke G Langendonk

Keyword(s):

Case Report ◽

Liver Injury ◽

Severe Liver ◽

Erythropoietic Protoporphyria ◽

Letter To The Editor

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A case of erythropoietic protoporphyria with severe liver damage

Kanzo ◽

10.2957/kanzo.51.175 ◽

2010 ◽

Vol 51 (4) ◽

pp. 175-182 ◽

Cited By ~ 1

Author(s):

Hiroaki Shimazaki ◽

Yuko Arima ◽

Takuji Nakano ◽

Michihito Murao ◽

Yoshifumi Nitta ◽

...

Keyword(s):

Liver Damage ◽

Severe Liver ◽

Erythropoietic Protoporphyria ◽

Severe Liver Damage

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A new ferrochelatase mutation combined with low expression alleles in a Japanese patient with erythropoietic protoporphyria

Clinical Science ◽

10.1042/cs1020501 ◽

2002 ◽

Vol 102 (5) ◽

pp. 501-506 ◽

Cited By ~ 3

Author(s):

Yumiko YASUI ◽

Shikibu MURANAKA ◽

Tsuyoshi TAHARA ◽

Ryo SHIMIZU ◽

Sonoko WATANABE ◽

...

Keyword(s):

Base Pair ◽

Japanese Patient ◽

Stop Codon ◽

Premature Stop Codon ◽

Amino Acid Position ◽

Molecular Defect ◽

Wild Type ◽

Erythropoietic Protoporphyria ◽

Base Pair Deletion ◽

Low Expression

We investigated the molecular defect of the ferrochelatase gene in a Japanese patient with erythropoietic protoporphyria (EPP), and identified a novel 16 base pair (574-589) deletion within exon 5. This deletion resulted in a frame-shift mutation and created a premature stop codon at amino acid position 198. The same molecular defect was also identified in his mother and a brother who had symptomatic EPP, but not in his father who was asymptomatic. The subjects with EPP were homozygous for the low expression haplotype, while his father was heterozygous for this haplotype. These results indicate that the combination of a 16 base pair deletion and low expression of the wild-type allelic variant is responsible for EPP in this pedigree.

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Preventive effect of urinary trypsin inhibitor on the development of liver fibrosis in mice

Experimental Biology and Medicine ◽

10.1258/ebm.2011.011173 ◽

2011 ◽

Vol 236 (11) ◽

pp. 1314-1321 ◽

Cited By ~ 2

Author(s):

Toru Kono ◽

Yurino Kashiwade ◽

Toshiyuki Asama ◽

Naoyuki Chisato ◽

Yoshiaki Ebisawa ◽

...

Keyword(s):

Liver Fibrosis ◽

Trypsin Inhibitor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Wild Type ◽

Long Term Effects ◽

Urinary Trypsin Inhibitor ◽

Severe Liver ◽

Fibrosis Marker

Urinary trypsin inhibitor (UTI) is a serine protease inhibitor produced in the liver that inhibits the production and activation of various cytokines, notably transforming growth factor- β (TGF- β), which are associated with the progression of liver fibrosis. However, the various roles of endogenous UTI in liver fibrosis have not been examined. This study, therefore, examined the long-term effects of UTI deficiency during both steady-state conditions and thioacetamide (TA)-induced liver fibrosis. Furthermore, the effects of continuous exogenous UTI administration were examined. Analyses of liver fibrosis marker, hyaluronic acid (HA), TGF- β concentrations and histological findings at 30 weeks of age showed that homozygous UTI-knockout (KO) mice had higher HA and TGF- β concentrations than did heterozygous UTI-KO mice and wild-type mice, although there was no histological evidence of liver fibrosis in these mice. TA treatment for 20 weeks also resulted in greater HA and TGF- β levels in homozygous mice than in heterozygous and wild-type mice. Furthermore, homozygous mice had more severe liver fibrosis based on histological analyses. HA and TGF- β levels were lower in homozygous UTI-KO mice that were continuously administered UTI versus those given distilled water. These findings indicate that UTI deficiency leads to the production of HA and hepatic TGF- β and that administering exogenous UTI can ameliorate these changes. We conclude that endogenous UTI is produced in the liver to suppress the production and activation of TGF- β and that administering exogenous UTI may be therapeutically beneficial for preventing liver fibrosis.

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