Elsevier

Blood Cells, Molecules, and Diseases

Volume 36, Issue 1, January–February 2006, Pages 33-40
Blood Cells, Molecules, and Diseases

Hereditary hyperferritinemia cataract syndrome in three unrelated families of western Greek origin caused by the C39 > G mutation of L-ferritin IRE

https://doi.org/10.1016/j.bcmd.2005.10.003Get rights and content

Abstract

Hereditary hyperferritinemia–cataract syndrome (HHCS) is a well-characterized autosomal dominant disease caused by mutations in the iron responsive element (IRE) of ferritin L-chain (FTL) mRNA. Mutations in the IRE result in reduced binding of the trans-acting iron regulatory proteins (IRPs) and hence in upregulation of ferritin L-chain synthesis. The disease is characterized by increased L-ferritin in serum and tissues and early onset of bilateral cataracts. Iron metabolism is normal, and there is no tissue iron overload. At least 25 nucleotide substitutions and deletions in the L-ferritin IRE have been described in families with HHCS, originating from diverse European, Australian and North American populations. We studied the molecular pathogenesis of HHCS in three unrelated kinderships of western Greek origin, with 19 affected members. We identified a relatively rare C39G mutation located in the hexanucleotide loop of L-ferritin IRE. Computational analysis of mRNA folding of mutant FTL IRE predicted that the C39 > G mutation leads to a rearrangement of base pairing in this critical region, which is likely to modify the IRP binding affinity. All subjects with HHCS were heterozygotes for the same C39G mutation. Clinical and laboratory phenotypes were described. Moreover, there was evidence of an association between this FTL IRE stem-loop mutation and very high ferritin levels. Our findings broaden the list of populations where HHCS has been described.

Introduction

Hereditary hyperferritinemia–cataract syndrome (HHCS) is clinically characterized by the combination of elevated serum L-ferritin and early onset of bilateral cataracts [1], [2], [3], [4]. Despite the five- to twenty-fold increase in serum L-ferritin levels, no significant effects on body iron metabolism have been observed [4]. Unlike hereditary hemochromatosis, serum iron and transferrin saturation remain normal or low. Hyperferritinemia can persist even in HHCS patients who develop iron deficiency anemia [4], [5].

Hereditary hyperferritinemia–cataract syndrome (OMIM #600886) is transmitted as an autosomal dominant disease resulting from mutations or deletions in the iron responsive element (IRE) of L-ferritin (FTL) gene, located in chromosome 19q13.3–q13.4 [6], [7], [8], [9] (Fig. 1, Fig. 2a).

At least 25 different mutations and deletions spanning the whole IRE structure are reported in families with HHCS. Sporadic cases due to de novo mutations have also been described [10], [11], [12]. Some of the mutations affect the loop that interacts directly with the IRPs, whereas other mutations affect the stems or the bulge of the IRE structure and modify its conformation (Fig. 2b) [13], [14].

The mechanism responsible for the onset of cataract in HHCS is not yet elucidated. Ferritin represents an abundant soluble protein in the lens even in normal conditions and 10–15-fold increase in the lens of HHCS patients was found [4], [15]. Increase in L-ferritin in the lens may affect the solubility of other lens proteins and lead to lens damage [15]. Alternatively, crystalline deposition of L-ferritin itself may trigger cataract development [16]. In HHCS, cataract is probably not congenital and develops in the first few years of life in an age-dependent manner [4].

HHCS has been described in families from diverse geographic areas [5], [17], [18], [19], [20]. Here, we described the first report of HHCS in 3 unrelated Greek families, originating from western Greece, with 19 affected members. Moreover, we identified a relatively rare C39 > G substitution located in the hexanucleotide loop of the L-ferritin IRE. Clinical and laboratory phenotypes of these subjects are described.

Section snippets

Subjects

Three index probands from 3 unrelated families of western Greek origin were referred for evaluation of persistently elevated serum ferritin levels. These probands as well as several members of their pedigrees underwent screening and interviewing for HHCS and other iron overload associated conditions. Clinical information on these subjects was described. Moreover, testing for biochemical markers of iron metabolism and genetic testing for HHCS and hemochromatosis was performed.

Results

Overall, at least 19/70 subjects were identified with HHCS in the 3 kinderships. Genetic testing for HHCS was performed in 9/19 clinically affected members total. All members with HHCS were heterozygotes for a C39 > G mutation in the FTL IRE stem-loop; while unaffected members were wild-type homozygotes (Fig. 3). Seventeen subjects had serum ferritin levels >900 μg/L; 12 subjects were diagnosed with bilateral cataract at an age younger than 40 years, with at least 1 subject at the age of 5

Discussion

This is the first report describing HHCS in Greek families, providing additional evidence for the worldwide distribution of the syndrome. Evidence on the true prevalence of HHCS is very limited. A population-based Australian study estimated a minimum prevalence of approximately 1:200,000 subjects [10]. However, screening of over 3000 blood donors with hyperferritinemia and 13,000 patients with cataract failed to identify mutations of the FTL IRE gene. It is of particular interest that all 3

Acknowledgment

This work was partly supported by the Greek Ministry of Education (Grant “Pythagoras”—EPEAEKII to N.S.).

References (41)

  • M. Cazzola et al.

    Hereditary hyperferritinemia–cataract syndrome: relationship between phenotypes and specific mutations in the iron-responsive element of ferritin light-chain mRNA

    Blood

    (1997)
  • M.E. Martin et al.

    A point mutation in the bulge of the iron-responsive element of the L ferritin gene in two families with the hereditary hyperferritinemia–cataract syndrome

    Blood

    (1998)
  • L. Garderet et al.

    Hereditary hyperferritinemia–cataract syndrome: a novel mutation in the iron-responsive element of the L-ferritin gene in a French family

    Am. J. Med.

    (2004)
  • W. Mikulits et al.

    Post-transcriptional control via iron-responsive elements: the impact of aberrations in hereditary disease

    Mutat. Res.

    (1999)
  • P. Aguilar-Martinez et al.

    A novel mutation in the iron responsive element of ferritin L-subunit gene as a cause for hereditary hyperferritinemia–cataract syndrome

    Blood

    (1996)
  • D.H. Mathews et al.

    Expanded sequence dependence of thermodynamic parameters improves prediction of RNA secondary structure

    J. Mol. Biol.

    (1999)
  • C. Ellervik et al.

    Prevalence of hereditary haemochromatosis in late-onset type 1 diabetes mellitus: a retrospective study

    Lancet

    (2001)
  • D. Bonneau et al.

    Bilateral cataract and high serum ferritin: a new dominant genetic disorder?

    J. Med. Genet.

    (1995)
  • D. Girelli et al.

    A linkage between hereditary hyperferritinaemia not related to iron overload and autosomal dominant congenital cataract

    Br. J. Haematol.

    (1995)
  • D. Girelli et al.

    Clinical, biochemical and molecular findings in a series of families with hereditary hyperferritinaemia–cataract syndrome

    Br. J. Haematol.

    (2001)
  • Cited by (17)

    • Hereditary hyperferritinemia-cataract syndrome

      2007, Journal of AAPOS
      Citation Excerpt :

      Based on these reports, chromosome 19q was implicated as the site most likely to contain the defect responsible for HHCS. Prior reports on HHCS have originated from Western Europe,1,2,4-15 North America,16-20 Australia,21,22 and India.23 These studies have also shown that distinct chromosomal mutations in the iron responsive element of the L-ferritin subunit are responsible for HHCS; these mutations prevent binding of iron (which provides negative feedback) and lead to the unregulated production of ferritin.

    View all citing articles on Scopus
    View full text