The BMP-SMAD pathway mediates the impaired hepatic iron metabolism associated with the ERFE-A260S variant.
Am J Hematol
; 94(11): 1227-1235, 2019 11.
Article
em En
| MEDLINE
| ID: mdl-31400017
ABSTRACT
The erythroferrone (ERFE) is the erythroid regulator of hepatic iron metabolism by suppressing the expression of hepcidin. Congenital dyserythropoietic anemia type II (CDAII) is an inherited hyporegenerative anemia due to biallelic mutations in the SEC23B gene. Patients with CDAII exhibit marked clinical variability, even among individuals sharing the same pathogenic variants. The ERFE expression in CDAII is increased and related to abnormal erythropoiesis. We identified a recurrent low-frequency variant, A260S, in the ERFE gene in 12.5% of CDAII patients with a severe phenotype. We demonstrated that the ERFE-A260S variant leads to increased levels of ERFE, with subsequently marked impairment of iron regulation pathways at the hepatic level. Functional characterization of ERFE-A260S in the hepatic cell system demonstrated its modifier role in iron overload by impairing the BMP/SMAD pathway. We herein described for the first time an ERFE polymorphism as a genetic modifier variant. This was with a mild effect on disease expression, under a multifactorial-like model, in a condition of iron-loading anemia due to ineffective erythropoiesis.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Sobrecarga de Ferro
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Proteínas Morfogenéticas Ósseas
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Hormônios Peptídicos
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Proteínas Smad
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Anemia Diseritropoética Congênita
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Fígado
Tipo de estudo:
Risk_factors_studies
Limite:
Adolescent
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Adult
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Child
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Female
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Humans
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Male
Idioma:
En
Revista:
Am J Hematol
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Itália