Hyperferritinemia Candidate Gene

Ferritin is a ubiquitous protein capable of storing iron in the cell cytosol. The stored iron is released and made available for cellular needs by the degradation of ferritin itself. Small amounts of ferritin are present in the bloodstream and consist of ferritin L, a glycosylated form of L called ferritin G, and traces of ferritin H. It is secreted primarily by macrophages, hepatocytes, and lymphoid cells, but most aspects of its secretion remain unknown. Serum ferritin has broad clinical utility primarily as an indicator of intracellular iron stores. The causes of increased serum ferritin are numerous, including primary and secondary iron overload disorders, but also conditions in which serum ferritin is increased disproportionately to the body's iron stores such as chronic liver disease, inflammatory and metabolic disorders that are frequently observed in the clinical setting. Therefore, the diagnosis of hyperferritinemia requires a systematic strategy including personal and family history, biochemical and instrumental tests. Recently, a second dominant form of genetic hyperferritinemia without iron overload or cataracts has been reported. Amino acid substitutions at positions 26, 27, and 30 in the heterozygous state in the L-ferritin A helix have been found in these patients. The resulting ferritin appears unusually susceptible to glycosylation, leading to serum glycosylated ferritin values consistently >90%. The reason for the development of hyperferritinemia and hyperglycosylation associated with these mutant forms of ferritin has not been established. It is probably related to increased secretion, but may also contribute to delayed clearance. Some cases of hyperferritinemia remain unexplained, however, and the currently unknown candidate gene that we think we have identified among responsible genes needs to be validated in a larger population of subjects with the listed characteristics.The main objective of the study is to sequence the candidate gene emerged from previous studies as mutated in 100 patients with the same clinical features. Subsequently, the candidate gene, if found mutated and therefore responsible, could be included in the routine genetic diagnosis of subjects suffering from hyperferritinemia without tissue iron overload.

Inclusion Criteria:Among patients referred to the Center for Rare Diseases of Monza will be enrolled only subjects with:ferritin > 1000 g / L in men and > 500 g / L,transferrin saturation <45%absence of hepatic iron overload, evaluated by liver biopsy or MRI, as indicated in the attached flow chart.Exclusion Criteria:Patients with hyperferritinemia attributable to:genetically determined causes [mutations in the HFE gene (homozygosity or heterozygosity for p.Cys282Tyr, homozygosity for p.His63Asp or compound heterozygosity for variants of p.Cys282Tyr and p. His63Asp), ferroportin and L-Ferritin gene mutations];presence of more than one component of metabolic syndrome (according to NCEP-ATPIII criteria: triglycerides >150 mg/dL, blood glucose >100 mg/dL, HDL <40 mg/dL in men and <50 mg/dL in women, waist circumference >102 cm in men and >88 cm in women; blood pressure ≥130/≥85 mm/Hg);alcohol intake >5 g/day chronic hepatitis,history of blood transfusion or parenteral iron treatment,late skin porphyria,hyperthyroidism,presence of cataracts or family history of early-onset cataractsacute or chronic inflammatory disorders.