Functional and Clinical Impact of NovelTmprss6Variants in Iron-Refractory Iron-Deficiency Anemia Patients and Genotype-Phenotype Studies

Abstract

Iron-refractory iron-deficiency anemia (IRIDA) is a rare autosomal-recessive disorder characterized by hypochromic microcytic anemia, low transferrin saturation, and inappropriate high levels of the iron hormone hepcidin. The disease is caused by variants in the transmembrane protease serine 6 (TMPRSS6) gene that encodes the type II serine protease matriptase-2, a negative regulator of hepcidin transcription. Sequencing analysis of the TMPRSS6 gene in 21 new IRIDA patients from 16 families with different ethnic origin reveal 17 novel mutations, including the most frequent mutation in Southern Italy (p.W590R). Eight missense mutations were analyzed in vitro. All but the p.T287N variant impair matriptase-2 autoproteotylic activation, decrease the ability to cleave membrane HJV and inhibit the HJV-dependent hepcidin activation. Genotype-phenotype studies in IRIDA patients have been so far limited due to the relatively low number of described patients. Our genotype-phenotype correlation analysis demonstrates that patients carrying two nonsense mutations present a more severe anemia and microcytosis and higher hepcidin levels than the other patients. We confirm that TMPRSS6 mutations are spread along the gene and that mechanistically they fully or partially abrogate hepcidin inhibition. Genotyping IRIDA patients help in predicting IRIDA severity and may be useful for predicting response to iron treatment.

Hepcidin in the diagnosis of iron disorders

“…53 Because of the highly dynamic and multifactorial regulation, a key practical message is that, in a given individual, the correct interpretation of hepcidin levels requires accurate knowledge of the overall clinical context (Table 1 8 This genetic disease, due to mutations in the hepcidin inhibitor TMPRSS6 (encoding matriptase-2), 30 is characterized by IDA with inappropriately normal or high hepcidin levels. 54,55 Thus, oral iron is ineffective and parenteral administration is needed to achieve at least a partial response. In classical IDA, hepcidin is suppressed below the limit of detection in biological fluids.…”

Modern iron replacement therapy: clinical and pathophysiological insights

“…Subjects homozygous for mutations in TMPRSS6, encoding the hepcidin inhibitor Matriptase-2, are affected by a rare genetic form of anemia named Iron Refractory Iron Deficiency Anemia (IRIDA, OMIM #206200) [64]. This condition should be suspected in patients presenting with IDA early in life, and poor or no response to oral iron without apparent cause [65,66]. Indeed, the biochemical hallmark of IRIDA is the presence of high (or inappropriately normal) serum hepcidin levels [25], which are pathogenetically relevant.…”

Toward Worldwide Hepcidin Assay Harmonization: Identification of a Commutable Secondary Reference Material

“…As a key player in iron metabolism, hepcidin holds great promise as the target of therapy and biomarker for diagnosis and monitoring of iron disorders (2 ). Hepcidin concentrations may be used for diagnosis of ironrefractory iron deficiency anemia (4,5 ), differentiation between iron deficiency anemia and anemia of chronic disease (2,6,7 ), guidance in safe iron supplementation (8 ), and as a companion diagnostic in novel therapies (9,10 ).…”