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CORRESPONDENCE
A Novel Mutation in the Iron Responsive Element of Ferritin L-Subunit Gene as a Cause for Hereditary
Hyperferritinemia-Cataract Syndrome
To the Editor:
The Hereditary hyperferritinemia-cataract syndrome was recently
described by Girelli et al.’ This new genetic disorder associates an
elevated serum ferritin level without iron overload, and autosomal
dominant congenital cataract. The same authors had consequently
identified a mutation in the iron responsive element (IRE) ofthe
Ferritin L-subunit gene.’ This mutation is a G to C substitution at
nucleotide 147 of the L-femtin gene sequence. These authors argued
that the mutation, situated in the 5-base sequence (CAGUG) that
characterizes the loop structure of the IRE would impair the normal
function of this loop in the iron-mediated regulation of ferritin biosynthesis. This would result in an upregulation of ferritin biosynthesis in affected subjects.
An 8-year-old boy was recently referred to our hospital department
because of the discovery of hyperferritinemia (1,000 wg/L). He had
no biological evidence of iron overload: serum iron and transfemn
saturation were normal. Blood cell counts and acute phase reactant
were also normal. He, as well as his father and grandfather, suffered
from hereditary cataract. His father had also hyperfemtinemia (780
,ug/L). His mother had normal ferritin levels and no cataract. Both
parents were of French origin.
We investigated three family members (father, mother, and son)
at the DNA level. DNAwas extracted from blood samples after
informed and written consent. We first tested the presence of the
by using the modified primer
mutation identified by Girelli et
described in their report. This primer creates an artificial site of
restriction for the enzyme Dde I. Using this method, the mutational
pattern was not found in the boy nor in his parents. We then tested
the 5’ UTR region of their L-femtin gene by single stand conformation (SSC) analysis, using the primers 5‘ UTR-F and 5’ UTR-R’ and
a’l
silver staining3(data not shown). The DNA from the young boy and
his father exhibited a different band pattern from the DNA from
the mother or a normal individual on this PCR amplified fragment
submitted to SSC analysis. These PCR fragments were subsequently
sequenced by automatic DNA sequencing. The sequence analysis
(Fig 1) identified an A to G substitution at position 146 of the LFerritin gene sequence (according to the numbering of the EMBL
sequence named HSAFL12). The mutation was present at the heterozygous state in the boy and his father, and could be found in both
strands of their DNA.
We have characterized a new mutation situated in the 5’UTR
sequence of the L-ferritin gene. This substitution is different from
the mutation previously described in this region and suspected to be
responsible for the hereditary hyperfemtinemia-cataract syndrome
in an Italian family. Therefore, the novel mutation described in this
report involves a nucleotide situated close to the previous one. It is
also included in the CAGUG loop sequence of IRE. The finding of
a novel mutation in this small DNA region gives further evidence
that mutational events in this loop may disturb the iron regulation
of ferritin levels, as it was first hypothesized by Girelli et al.’ Furthermore our data indicate that the Hereditary Hyperferritinemia-cataract syndrome does not have an unique mutational origin and that
other affected families could have different base substitutions in this
DNA region.
ACKNOWLEDGMENT
The authors are grateful to Drs Clot and Eliaou for allowing us
to use their automatic DNA sequencer, and to Odile Avinens for
technical assistance.
P. Aguilar-Martinez
C. Biron
C . Masmejean
P. Jeanjean
J-F Schved
Laboratory of Hematology
Hospital Saint-Eloi
Montpellier, France
REFERENCES
Fig 1. Automatic DNA sequence analysis.P, patient (affectedboy);
N. normal individual. In thenormal sequence, the nucleotideat position 146 (EMBL sequence HSAFL12) is an A. The mutation of the
patient (shown by an asterisk above the ambiguous nucleotide)
changes an A to G on the paternal chromosome.
Blood, Vol 88,No 5 (September I), 1996:pp 1895-1903
1. Girelli D, Corrocher R, Bisceglia L, Olivieri 0, De Franceschi
L, Zelante L, Gasparini P: Molecular basis for the recently described
hereditary hyperfemtinemia-cataract syndrome: A mutation in the
iron-responsive element of ferritin L-subunit gene (The “Verona
mutation”). Blood 86:4050, 1995
2. Girelli D, Olivieri 0, De Franceschi L, Corrocher R, Bergamaschi G, Cazzola M: Linkage between hereditary hyperferritinaemia not related to iron overload and autosomal dominant congenital cataract. Br J Haematol 90931, 1995
3. Cai QQ, Touitou I: Excess of primer may dramatically affect
SSCP efficiency. Nucleic Acids Res 21:3909, 1993
1895
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
1996 88: 1895
A novel mutation in the iron responsive element of ferritin L-subunit
gene as a cause for hereditary hyperferritinemia-cataract syndrome
[letter; comment]
P Aguilar-Martinez, C Biron, C Masmejean, P Jeanjean and JF Schved
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