In β-thalassemia, accumulated free α-globin forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality control systems mitigate β-thalassemia pathophysiology by degrading toxic free α-globin, although the associated mechanisms are poorly understood. We show that loss of the autophagy-activating Unc-51–like kinase 1 (Ulk1) gene in β-thalassemic mice reduces autophagic clearance of α-globin in red blood cell precursors and exacerbates disease phenotypes, whereas inactivation of the canonical autophagy-related 5 (Atg5) gene has relatively minor effects. Systemic treatment with the mTORC1 inhibitor rapamycin reduces α-globin precipitates and lessens pathologies in β-thalassemic mice via an ULK1-dependent pathway. Similarly, rapamycin reduces free α-globin accumulation in erythroblasts derived from CD34+cells of β-thalassemic individuals. Our findings define a drug-regulatable pathway for ameliorating β-thalassemia.

Juvenile hemochromatosis (JH) is a rare autosomal recessive disorder of iron metabolism, genetically heterogeneous. In JH, symptomatic organ involvement occurs as early as the second decade of life. Heart failure and/or arrhythmias are the most frequent causes of death. Phlebotomy is the safest, most effective, and most economic therapeutic approach in hemochromatosis patients but is not indicated during the treatment of severe congestive heart failure with unstable hemodynamic status. The treatment of iron overload in these prohibitive clinical situations has to be carried out using iron chelators. We report a case of heart failure in the setting of unrecognized juvenile hemochromatosis successfully treated by the simultaneous administration of deferoxamine and deferiprone. To our knowledge, this is the first patient affected by JH treated with combined chelation regimen.

SummaryTransmembrane Protease, Serine 6 (TMPRSS6) has an important role in iron homeostasis and its mutations, performed in TMPRSS6-deficient mice, have been recently associated with iron-refractory iron deficiency anaemia (IRIDA). Several variants of TMPRSS6 have been already identified; however the role of polymorphisms and TMPRSS6 haplotypes, causing iron deficiency anaemia, have not yet been investigated. This study sequenced the TMPRSS6 gene in 16 subjects with IRIDA phenotype and identified 27 DNA polymorphisms. Eight single nucleotide polymorphisms and four haplotypes were significantly associated with iron-refractory anaemia (P < 0AE001). Our preliminary results suggest a possible association between specific haplotypes of TMPRSS6 and IRIDA.