C29G in the iron-responsive element of l-ferritin: a new mutation associated with hyperferritinemia-cataract

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Abstract

Hyperferritinemia-cataract syndrome (HHCS) is a dominant disorder characterized by high serum ferritin and early onset of bilateral cataract. The disorder is caused by mutations in the iron-responsive element (IRE) of l-ferritin, which disrupt the postranscriptional control of l-ferritin synthesis. Here, we report a new (C>G) mutation which affects base 29 in the loop (c.-169C>G), previously unrecognized as essential for the stem loop stability. The mutation was identified in two members of an Italian family. Computer modeling and electrophoretic mobility shift assay (EMSA) confirm a decreased affinity of the C29G IRE for IRPs control proteins.

Introduction

Hyperferritinemia-cataract syndrome (HHCS) is a genetic dominant disorder associated with bilateral cataract and increased serum ferritin in the absence of iron overload. Mutations in iron-responsive element (IRE) of the l-ferritin promoter result in constitutive, iron-independent ferritin expression [1], [2]. Several nucleotide substitutions [3] and rare deletions [4], [5] affect the l-ferritin IRE in this syndrome. The vast majority of mutations cluster in the highly conserved terminal loop (5′CAGUG), especially positions 39–41 of the IRE or close to the unpaired cytosine 32 (positions 32, 33) that forms a lateral bulge in the IRE stemlike structure [3].

As we are in a hemochromatosis referral center, we occasionally identify subjects with this disorder, who are referred for hyperferritinemia [3]. In the last years, 14 HHCS families were diagnosed out of 1100 samples referred for hemochromatosis. Here, we describe a family of central Italian ancestry, presenting a new IRE mutation.

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Patients and methods

The proband (I-1) is a 40-year-old male with an unremarkable history. He had a reduction of visual acuity, because of bilateral lens opacities discovered since many years. Blood tests were performed because of the occasional finding of elevated serum ferritin in his infant child (II-1). Transferrin saturation, hemoglobin levels, and hematological parameters were normal. He had total bilirubin of 1.29 (indirect 0.94 mg/ml), ALT 57 IU/l, γGT 141 IU/l, hypercholesterolemia (276 mg/dl), and

Results and Discussion

Hemochromatosis mutations were negative in all subjects. Nucleotide sequencing of IRE of l-ferritin identified a c.-169C>G (29C>G in the IRE) heterozygous mutation (position 169 from the ATG) (Fig. 1A) in I-1 and II-1. I-2 was normal. I-1 was also homozygous for the A(TA)7TAA pattern in the uridine 5′-diphosphate-glucuronosyl-transferase promoter (not shown), compatible with Gilbert disease [8]. The C29G mutation was never reported before in HHCS and was not found in a large series of HHCS

Acknowledgements

This study was partially supported by Telethon-Italy grant GP00255Y01 and grants (PRIN and FIRB) from Italian Ministry of Instruction, University and Research to C.C., MIUR-FIRB grants 2001 and Telethon-Italy grant GP-0075Y01 to S.L.

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