Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 4020-4021
CORRESPONDENCE
Description of a New Mutation in the L-Ferritin Iron-Responsive
Element Associated With Hereditary Hyperferritinemia-Cataract Syndrome
in a Spanish Family
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LETTER |
To the Editor:
The hereditary hyperferritinemia cataract syndrome (HHCS) is
characterized by an elevated serum ferritin level without iron overload, and autosomal dominant congenital bilateral cataract. In
1995, Girelli et al1 identified a first mutation in the 5'
untranslated region of the L-subunit ferritin gene of an Italian family
suffering from HHCS. This mutation was located in a critical sequence
of the stem-loop motif known as iron-responsive element (IRE). IRE is a
highly conservative structure that has been found in the 5'
untranslated region of all ferritin mRNAs, as well as in different
regulatory areas of other iron-related homeostasis genes.2
IRE is constituted by a six-nucleotide loop of consensus sequence
5'-CAGUGN-3' and a paired stem with a small asymmetrical bulge. This
structure has been shown to be critical for the posttranscriptional regulation of ferritin synthesis by means of IRE-binding protein (IRP).
Subsequent changes in the IRE sequence have been described in several
families from different countries of Europe in which HHCS was
diagnosed. A number of IRE sequence substitutions have been shown to
reduce protein binding affinity of IRP in vitro, producing L-ferritin
accumulation as nonfunctional L-chain homopolymers either in
lymphoblastoid cell lines or the lens.3 These
findings have suggested that mutations in the IRE constitute the
molecular basis in HHCS.
A healthy 3-month-old boy showed persistent hyperferritinemia (1,022 to
2,350 µg/L) in routine blood examinations when he was referred to our
pediatric department with an infection. Serum iron and transferrin
saturation levels were normal. His father, grandmother, aunt, and two
cousins also suffered from hyperferritinemia (989 to 1,770 µg/L).
Additionally, all except the proband suffered from congenital bilateral
cataract, with visual symptoms appearing during the first decade.
However, only the grandmother required surgery at the age of 60 (Fig
1). The visual acuity of the remaining members affected by cataract was corrected with eyeglasses.
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| Fig 1.
Pedigree of the family with HHCS. (Circles) Females;
(squares) males; (closed symbols) affected members. Arrow indicates the
proband. (a) Age at time of our observation (y, years; m, months). (b)
Serum L-ferritin levels (µg/L). (c) Bilateral cataract status (C,
cataracts; NC, no cataracts).
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| Fig 2.
Sequence and proposed structure of the ferritin L-subunit
IRE mRNA. The mutation found in the 5' UGC bulge is indicated.
Numbering is from the first transcripted nucleotide.
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To carry out the molecular analysis of the L-chain ferritin gene, a
754-bp DNA fragment including the 5' untranslated region, exons 1 and
2, as well as intron 1 and part of intron 2 was amplified by polymerase
chain reaction (PCR). Amplification primers were based on the
L-ferritin sequence published by Santoro et al4 (GenBank
accession no. X03742). DNA fragments were subsequently cloned and more
than 10 clones from each patient were sequenced by automated DNA
sequencing. Sequence analysis identified a point mutation, C to T, at
position 33, according to the numbering of Cazzola et al,5
in a half of the analyzed clones of all patients as an average (GenBank
accession no. AF117958). This nucleotide substitution is
located at the consensus three nucleotide bulge structure, positions
31-33 (Fig 2).
Correlation between genotype and phenotype has been suggested for
HHCS.5 Mutations placed at the conserved loop are
associated to higher ferritin concentrations and more severe cataracts
than those found in the three-nucleotide motif forming the
IRE bulge. Furthermore, nucleotide changes located at the lower stem
have been associated with asymptomatic cataract and serum ferritin levels in the range of 350 to 650 µg/L. Therefore, three nucleotide substitutions have been described at the IRE bulge motif. The mutation
termed Pavia 1, G to A at position 32, was associated with similar
serum ferritin levels to those found in our studied family and a
similar mild cataract with visual symptoms appearing during childhood.5 More recently, two French families have been described bearing the same G to T substitution at position 32, though displaying a marked variability in the age of onset of cataract
between members of the two families.6
In conclusion, we have characterized a new mutation placed at the IRE
sequence of the L-ferritin gene. This mutation is located at the bulge
motif close to two different point substitutions previously described
in three families that showed similar phenotypic characteristics to
those found by us. These findings are in agreement with the observed
correlation between genotype and phenotype in HHCS and increase the
genotypic diversity of this disease.
Antonio Balas
Maria
Jose Aviles
Felix Garcia-Sanchez
Jose L. Vicario
Histocompatibility and Molecular Biology Laboratory
Regional
Transfusion Centre
Madrid, Spain
Aurea Cervera
Paediatric Department
Mostoles General Hospital
Madrid,
Spain
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REFERENCES |
1.
Girelli D, Corrocher R, Bisceglia L, Olivieri O, De Franceschi L, Zelante L, Gasparini P:
Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: A mutation in the iron-responsive element of ferritin L-subunit gene (the "Verona mutation").
Blood
86:4050, 1995[Abstract/Free Full Text]
2.
Klausner RD, Rouault TA, Harford JB:
Regulating the fate of mRNA: The control of cellular iron metabolism.
Cell
72:19, 1993[Medline]
[Order article via Infotrieve]
3.
Levi S, Girelli D, Perrone F, Pasti M, Beaumont C, Corrocher R, Albertini A, Arosio P:
Analysis of ferritins in lymphoblastoid cell lines and in the lens of subjects with hereditary hyperferritinemia-cataract syndrome.
Blood
91:4180, 1998[Abstract/Free Full Text]
4.
Santoro C, Marone M, Ferrone M, Costanzo F, Comolbo M, Minganti C, Cortese R, Silengo L:
Cloning of the gene coding for human L apoferritin.
Nucleic Acids Res
14:2863, 1986[Abstract/Free Full Text]
5.
Cazzola M, Bergamaschi C, Tonon L, Arbustini E, Grasso M, Vercesi E, Barosi G, Bianchi PE, Cairo G, Arosio P:
Hereditary hyperferritinemia-cataract syndrome: Relationship between phenotypes and specific mutations in the iron-responsive element of ferritin light-chain mRNA.
Blood
90:814, 1997[Abstract/Free Full Text]
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Martin ME, Fargion S, Brissot P, Pellat B, Bamont C:
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
91:319, 1998[Abstract/Free Full Text]
