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Blood, Vol. 91 No. 1 (January 1), 1998:
pp. 367-368
CORRESPONDENCE
Hereditary Hyperferritinemia-Cataract Syndrome: Two Novel
Mutations in the L-Ferritin Iron-Responsive Element
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LETTER |
To the Editor:
Cazzola et al1 recently reported two kindreds with
hereditary hyperferritinemia cataract syndrome (HHCS) associated with
novel point mutations within a regulatory stem-loop motif in the
L-ferritin mRNA termed the iron-responsive element (IRE). Affected
individuals showed a characteristic clinical phenotype of elevated
serum ferritin concentration and cataract developing early in life. The
proposed pathogenesis of this disorder is that nucleotide substitutions
within the IRE disrupt its specific interaction with the cytoplasmic
iron regulatory protein (IRP). Failure of optimal IRP-IRE binding in
turn leads to failure of suppression of L-ferritin translation.
There are now increasing numbers of reports that describe the
genotype-phenotype relationship in kindreds with naturally
occurring IRE mutations, and as Cazzola et al1 report, the
phenotype varies with the position of the mutation in the IRE. These
descriptions now provide clinical data that support the
structural model of the IRE-IRP interaction deduced from in vitro
binding studies using artificially created IRE mutants.2-4
We have identified two further kindreds with HHCS and novel mutations
in the L-ferritin IRE that further support this model.
Kindred I.
The 51-year-old male proband of English origin developed visual
symptoms in his mid-thirties from cataracts, but was otherwise
asymptomatic. Investigations revealed a serum ferritin of 1,389 µg/L
but normal transferrin saturation. Similar abnormalities were noted in
the proband's sister, and liver biopsy specimens from both these
individuals showed no iron overload. Sequencing of genomic DNA from the
proband showed a heterozygous point mutation that corresponded to a +39
C  U substitution in the L-ferritin mRNA.
Kindred 2.
The 42-year-old female proband of English origin was investigated for
anemia detected at one of her regular blood transfusion sessions.
Although her red cell indices and transferrin saturation were
consistent with mild iron deficiency, her serum ferritin was
elevated at 1,020 µg/L. The proband herself had had previous surgical
extraction of cataracts, and there were premature cataracts in 8 other
family members. The son of the proband required cataract extraction at
5 years old. Hyperferritinemia was confirmed only in family members
with cataract. Analysis of genomic DNA also showed a heterozygous point
mutation, this time corresponding to a +36 C A substitution in the
L-ferritin mRNA. This substitution created an Mse I restriction
site within the amplified sequence, and restriction digests from
additional family members confirmed that the substitution segregated
with the hyperferritinemia-cataract phenotype.
The nucleotide substitutions detected in kindreds 1 and 2 lie in the
apical loop and upper stem of the IRE, respectively (Fig
1). We note that in both kindreds
individuals display a severe phenotype, and this is consistent with the
observations of Cazzola et al that mutations near the apex of the IRE
result in higher serum ferritin concentrations and denser cataracts.
These results also comply with data from in vitro binding studies;
nucleotide substitutions in the apical loop of the IRE dramatically
reduce IRP affinity, consistent with its putative role as the IRP
binding site.2,3 Individuals from kindred 1 with a
naturally occurring mutation at this site are therefore expected to
have a severe defect in L-ferritin regulation. In the case of kindred
2, artificially created nucleotide substitutions in the IRE upper stem
exert a profound effect on IRP binding in vitro, but only if
complementary base pairing in the stem is disrupted.4
Pairing of nucleotides may facilitate IRE-IRP binding by maintaining an
optimum secondary structure of the IRE. The severe phenotype of kindred
2, who have a naturally occurring noncomplementary nucleotide
substitution close to the IRP binding site, may therefore reflect a
broader structural derangement of the IRE.
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| Fig 1.
Schematic representation of the L-ferritin IRE adapted
from Cazzola et al showing the updated distribution of genotypic
abnormalities in HHCS. Substitutions +39 C U in kindred 1 and
+36 C A lie within the apical loop and upper stem, respectively.
(Adapted and reprinted with permission.1)
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Our kindreds help clarify the relationship between genotype and
phenotype in HHCS, and the description of two novel mutations
illustrates the increasing genotypic diversity of this disorder. The
severity of the phenotype of our patients and the position of the
nucleotide substitution support the existing models of IRE-IRP
interaction.
A.D. Mumford
T. Vulliamy
J. Lindsay
Imperial College School of
Medicine
Hammersmith Hospital
London, UK
A. Watson
Stoke Mandeville Hospital NHS trust
Aylesbury, Bucks,
UK
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REFERENCES |
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Cazzola M,
Bergamaschi G,
Tonon L,
Arbustini E,
Grasso M,
Vercesi E,
Baroi G,
Bianchi PE,
Cairo G,
Arosio P:
Hereditary hyperferritinaemia-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]
2.
Bettany AJE,
Eisenstein RS,
Munro HN:
Mutagenesis of the iron-regulatory element further defines a role for RNA secondary structure in the regulation of ferritin and transferrin receptor expression.
J Biol Chem
267:16531,
1992[Abstract/Free Full Text]
3.
Jaffrey SR,
Haile DJ,
Klausner RD,
Harford JB:
The interaction between the iron-responsive element and its cognate RNA is highly dependent upon both RNA sequence and structure.
Nucleic Acids Res
21:4627,
1993[Abstract/Free Full Text]
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Leibold EA,
Laudano A,
Yu Y:
Structural requirements of iron-responsive element for binding of the protein involved in both transferrin receptor and ferritin mRNA post-transcriptional regulation.
Nucleic Acids Res
18:1819,
1990[Abstract/Free Full Text]
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