IRIDA Phenotype in TMPRSS6 Monoallelic-Affected Patients: Toward a Better Understanding of the Pathophysiology

Abstract

Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive inherited form of iron deficiency anemia characterized by discrepantly high hepcidin levels relative to body iron status. However, patients with monoallelic exonic TMPRSS6 variants have also been reported to express the IRIDA phenotype. The pathogenesis of an IRIDA phenotype in these patients is unknown and causes diagnostic uncertainty. Therefore, we retrospectively summarized the data of 16 patients (4 men, 12 women) who expressed the IRIDA phenotype in the presence of only a monoallelic TMPRSS6 variant. Eight unaffected relatives with identical exonic TMPRSS6 variants were used as controls. Haplotype analysis was performed to assess the (intra)genetic differences between patients and relatives. The expression and severity of the IRIDA phenotype were highly variable. Compared with their relatives, patients showed lower Hb, MCV, and TSAT/hepcidin ratios and inherited a different wild-type allele. We conclude that IRIDA in monoallelic TMPRSS6-affected patients is a phenotypically and genotypically heterogeneous disease that is more common in female patients. We hypothesize that allelic imbalance, polygenetic inheritance, or modulating environmental factors and their complex interplay are possible causes. This explorative study is the first step toward improved insights into the pathophysiology and improved diagnostic accuracy for patients presenting with IRIDA and a monoallelic exonic TMPRSS6 variant.

Keywords: IRIDA; anemia; heterozygous TMPRSS6; iron; monoallelic TMPRSS6; phenotype.

Figure 1

Schematic view of hepatic hepcidin regulation by BMP/SMAD pathway and proposed potential candidate genes contributing to polygenetic inheritance in monoallelic IRIDA. Expression of hepcidin is regulated via the BMP/SMAD pathway, which is activated by BMP receptors that bind with BMP coreceptor hemojuvelin (HJV), leading to phosphorylation and translocation of the intracellular SMAD proteins to the nucleus. Here they act as transcription factors increasing HAMP mRNA transcription. Hepcidin expression via this pathway is modulated by three main mechanisms: erythropoiesis, inflammation, and iron (stored and circulating). Potential candidate genes in these pathways contributing to polygenetic inheritance are indicated by numbers (1 to 7). It is conceivable that gain of function mutations of positive regulatory factors and loss of function of inhibitors of the BMP/SMAD pathway (e.g., ACVR1 (ALK2)) can lead to an overactivation of the hepcidin response, leading to instability of the BMP pathway and, consequently, to a potential IRIDA phenotype: red clouds, loss of function (LoF); yellow stars, gain of function (GoF). Proposed genes are displayed by number: (1) FKBP1a (FKBP prolyl isomerase 1A) (LoF), (2) TMPRSS6 (transmembrane serine protease 6) (LoF), (3) BMPR1 (bone morphogenetic protein receptor type 1) (GoF), (4) TFR2 (transferrin receptor type 2) (GoF), (5) HFE (homeostatic iron regulator) (GoF), (6) HJV (hemojuvelin) (GoF), and (7) HAMP (hepcidin antimicrobial peptide) (GoF). Act-B, activin B; ERFE, erythroferrone; IL-6, interleukin 6; Fe³⁺-Tf, transfferin-bound iron; TfR, transferrin receptor; JAK2, Janus kinase 2—inhibiting effect.

Figure 2

Proposed model for the potential effect of environmental and (epi)genetic factors on IRIDA phenotype expression in TMPRSS6 monoallelic-affected subjects. Expression of IRIDA phenotype displayed as a sliding scale. The more to the right, the more pronounced the phenotype. Presence of modulating factors, including environmental and (epi)genetic factors, contribute to a more severe phenotype (right part of arrow). Treatment can improve phenotype (left part of arrow). Model is illustrated by two patients: ID 11, presented with Giardia lamblia infection and severe anemia. After antibiotic treatment, anemia improved but still persisted; ID 12, suffered from heavy menstrual bleedings, which stopped after starting gonadorelin antagonist. In combination with IV iron administration, IRIDA phenotype became less pronounced.