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Analysis of Ferritins in Lymphoblastoid Cell Lines and in the Lens of
Subjects With Hereditary Hyperferritinemia-Cataract Syndrome
Sonia Levi,
Domenico Girelli,
Federica Perrone,
Marcella Pasti,
Carole Beaumont,
Roberto Corrocher,
Alberto Albertini, and
Paolo Arosio
From Dibit, Institute H. San Raffaele, Milano, Italy; Institute of
Medical Pathology, University of Verona, Verona, Italy; Cattedra di
Chimica, University of Brescia, Brescia, Italy; and INSERM U409,
Faculté Bichat, Paris, France.
Hereditary hyperferritinemia-cataract syndrome (HHCS) is an
autosomal and dominant disease caused by heterogeneous mutations in the
iron responsive element (IRE) of the 5 untranslated flanking region of ferritin L-chain mRNA, which reduce the binding to the trans
iron regulatory proteins and make L-chain synthesis constitutively upregulated. In the several families identified so far, the serum and
tissue L-ferritin levels are fivefold to 20-fold higher than in
nonaffected control subjects, iron metabolism is apparently normal, and
the only relevant clinical symptom is early onset, bilateral cataract.
Some pathogenetic aspects of HHCS remain obscure, with particular
reference to the isoferritins produced by HHCS cells, as well as the
mechanism of cataract formation. We analyzed lymphoblastoid cell lines
obtained from two nonaffected control subjects and from HHCS patients
carrying the substitution A40G (Paris-1), G41C (Verona-1), and the
deletion of the residues 10-38 (Verona-2) in the IRE structure.
Enzyme-linked immunosorbent assays specific for the H- and L-type
ferritins showed that L-ferritin levels were up to 20-fold higher in
HHCS than in control cells and were not affected by iron
supplementation or chelation. Sequential immunoprecipitation
experiments of metabolically-labeled cells with specific antibodies
indicated that in HHCS cells about half of the L-chain was assembled in
L-chain homopolymers, which did not incorporate iron, and the other
half was assembled in isoferritins with a high proportion of L-chain.
In control cells, all ferritin was assembled in functional
heteropolymers with equivalent proportion of H- and L-chains. Cellular
and ferritin iron uptake was slightly higher in HHCS than control
cells. In addition, we analyzed the lens recovered from cataract
surgery of a HHCS patient. We found it to contain about 10-fold more
L-ferritin than control lens. The ferritin was fully soluble with a low
iron content. It was purified and partially characterized.
Our data indicate that: (1) in HHCS cells a large proportion of
L-ferritin accumulates as nonfunctional L-chain 24 homopolymers; (2)
the concomitant fivefold to 10-fold expansion of ferritin
heteropolymers, with a shift to L-chain-rich isoferritins, does not
have major effects on cellular iron metabolism; (3) L-chain
accumulation occurs also in the lens, where it may induce cataract
formation by altering the delicate equilibrium between other
water-soluble proteins (ie, crystallins) and/or the antioxidant
properties.
Blood, Vol. 91 No. 11 (June 1), 1998:
pp. 4180-4187
© 1998 by The American Society of Hematology.
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