Hereditary Hyperferritinemia Cataract Syndrome Research Articles

Síndrome hereditario de hiperferritinemia y catarata

This report describes a family with hereditary hyperferritinemia cataract syndrome. Inheritance is autosomal dominant and clinical characteristics of this syndrome are familial cataracts of early development and elevated serum ferritin levels but otherwise normal iron studies and haematological parameters. It is important to increase awareness of this entity in order to diagnose new cases and avoid unnecessary diagnostic tests and inadequate treatments.

Hereditary hyperferritinemia-cataract syndrome

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a recently recognized syndrome characterized by dominantly inherited, early-onset cataracts and elevated serum ferritin. The opacities are caused by elevated ferritin protein within the crystalline lens and usually become symptomatic in the second to fourth decade of life. Routine laboratory tests can establish this diagnosis. We report two unrelated cases that presented in the United States.

A novel deletion in theFTL gene causes hereditary hyperferritinemia cataract syndrome (HHCS) by alteration of the transcription start site

Hereditary hyperferritinemia cataract syndrome (HHCS) is characterized by distinctive cataracts and high serum ferritin in the absence of iron overload. It is caused by mutations in the iron response element (IRE) of the Ferritin Light Chain (FTL) gene. Here we investigate the genetics of HHCS in a three generation Australian kindred with typical HHCS ocular lens morphology and high ferritin levels. Initial sequencing of the IRE failed to detect any mutations. Sequencing of the entire gene including the promoter region revealed a novel 25 bp deletion upstream of the IRE abolishing the transcription start site. In lymphoblastoid cells, the deletion allele was transcribed from an alternate start site within the lower stem of the IRE and mutation carriers had high cellular L-ferritin levels. This novel deletion in the promoter encompassing the transcription start site of the FTL gene is responsible for HHCS in this kindred. The initial primers for amplifying the IRE similar to those used by other researchers failed to detect this mutation. Therefore the genomic region assessed in HHCS cases for diagnosis should be expanded to include mutations of this type.

Dual diagnoses of hereditary hyperferritinaemia-cataract syndrome and hereditary haemochromatosis

A 30-year-old woman was found to have hyperferritinaemia after presenting with menorrhagia and lethargy. Serum iron studies did not confirm iron overload. Further investigations revealed two distinct genetic mutations of iron haemostasis--homozygosity for C282Y mutation of the HFE gene on chromosome 6 and heterozygosity for A40G mutation in the iron response element of ferritin light chain on chromosome 19. These mutations are responsible for the diseases hereditary haemochromatosis (autosomal recessive) and hereditary hyperferritinaemia-cataract syndrome (autosomal dominant) respectively. This is the first description of such a patient.

The role of iron regulatory proteins in mammalian iron homeostasis and disease

Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are mammalian proteins that register cytosolic iron concentrations and post-transcriptionally regulate expression of iron metabolism genes to optimize cellular iron availability. In iron-deficient cells, IRPs bind to iron-responsive elements (IREs) found in the mRNAs of ferritin, the transferrin receptor and other iron metabolism transcripts, thereby enhancing iron uptake and decreasing iron sequestration. IRP1 registers cytosolic iron status mainly through an iron-sulfur switch mechanism, alternating between an active cytosolic aconitase form with an iron-sulfur cluster ligated to its active site and an apoprotein form that binds IREs. Although IRP2 is homologous to IRP1, IRP2 activity is regulated primarily by iron-dependent degradation through the ubiquitin-proteasomal system in iron-replete cells. Targeted deletions of IRP1 and IRP2 in animals have demonstrated that IRP2 is the chief physiologic iron sensor. The physiological role of the IRP-IRE system is illustrated by (i) hereditary hyperferritinemia cataract syndrome, a human disease in which ferritin L-chain IRE mutations interfere with IRP binding and appropriate translational repression, and (ii) a syndrome of progressive neurodegenerative disease and anemia that develops in adult mice lacking IRP2. The early death of mouse embryos that lack both IRP1 and IRP2 suggests a central role for IRP-mediated regulation in cellular viability.

Hiperferritinemia familiar y cataratas congénitas asociadas a mutación del gen HFE. Dos nuevas familias españolas y una nueva mutación (A37T: «Zaragoza»)

Nuclear congenital cataracts associated with hyperferritinemia--hereditary hyperferritinemia cataract syndrome (HHCS)--without clinical or biochemical signs of iron overload have been recently described in several Spanish families. This HHCS is associated with mutations in the gene of ferritin subunit L, located in chromosome 19. We describe 2 new families with HHCS, one of them presenting a new L-ferritin mutation (A37T: -Zaragoza-). Patients and probands were studied according to the Anemia Unit protocol: complete blood count, biochemical profile (diabetes, hepatic and renal), hepatic serologies, iron metabolism (iron, transferrin, ferritin, transferrin saturation, reactive C protein) and mutation HFE gene studies (C282Y, H63D). All of them were sent to the Ophthalmology Service for cataract study. L-ferritin mutational scanning was performed by denaturing high performance liquid chromatography (DHPLC). Samples displaying an altered elution profile, as compared to a wild type control, were directly sequenced for the precise characterization of the L-ferritin mutation. Family A proband was a 54 year-old-female, with cataracts, ferritin level: 942 pg/I, transferrin saturation: 14%, HFE gen study: H63D/H63D; L-ferritin gene study: C33T mutation/-. Her two sons had cataracts, hyperferritinemia (1607, and 1188 pg/I, respectively), normal transferrin saturation (40% and 9%), HFE gene study: H63D/N; and L-ferritin gen study: C33T/-. Family B proband was a 39 year-old-female, with cataract, ferritin level: 636 pg/I, transferrin saturation: 25%, HFE gene study: H63D/N; and L-ferritin gene study: A37T/-. Her two sons, sister, brother and nephew, who were affected with A37T mutation, showed hyperferritinemia (883, 747, 835, 613 and 1396 pg/I) with normal transferrin saturation levels (17%, 34%, 25%, 18% and 24%); but the ferritin levels of those non-affected were normal (35 and 50 pg/I). HHCS is a dominant autosomic condition, with a possible world-wide distribution,which should be included in the differential diagnosis of hyperferritinemia studies. It is important to suspect it in order to avoid wrong treatment.

Microelectronic DNA chip for hereditary hyperferritinemia cataract syndrome, a model for large-scale analysis of disorders of iron metabolism

Hereditary hyperferritinemia cataract syndrome (HHCS) is caused by mutations in the regulatory iron responsive element (IRE) in the 5'UTR of the L-ferritin transcript that reduce binding affinity to the iron regulatory proteins (IRPs) and lead to a constitutive upregulation of the protein in tissue and serum. Twenty-nine mutations have been reported within the L-ferritin (FTL) IRE sequence, 21 of which were available to us. In addition, we included in this study three new mutations. Thus, we analyzed 24 mutations spanning over a DNA stretch of 48 nucleotides, including four deletions 2-29 nucleotides long and 20 substitutions, seven of which were conservative transversions. With this unique experimental model we developed a microchip diagnostic platform for identifying known molecular defects in the L-ferritin IRE structure with a microelectronic array approach, which we optimized after studying the effects of various parameters. The system enables electronic deposition of biotinylated amplicons to selected pads. Under optimized conditions, no cross-hybridization was found, even for mutations that affected the same or adjacent nucleotide positions. The same cartridge could be serially hybridized with all the 24 reporter probe sets, which allowed correct genotyping right up until the end of the analysis. Extensive validation on 200 samples in a blinded fashion gave total concordance of results. This pilot study represents a first step toward developing a diagnostic microchip for large-scale analyses for epidemiological studies and screening of mutations associated with iron disorders.

Hereditary Hyperferritinemia Cataract Syndrome: Ocular, Genetic, and Biochemical Findings

To describe the cataract morphology and genetic and biochemical findings in a four-generation family with hereditary hyperferritinemia cataract syndrome (HHCS). Family members of the proband with HHCS were investigated. DNA sequencing was carried out to identify the iron responsive element (IRE) of the L-ferritin gene in affected and non-affected family members. Molecular modeling allowed prediction of the structure of the mutant IRE in affected cases. Serum ferritin and transferrin saturation were determined using standard methods. All family members underwent slit lamp examination by an ophthalmologist to document presence of cataract or lens status. Cataract morphology was documented where present. This family with HHCS had the genetic heterozygous mutation G32C in the IRE of the L-ferritin mRNA. Lens opacities were detectable in young members of the family, and morphology of cataracts was consistent with previous reports. Biochemical testing demonstrated high serum ferritin levels in affected individuals. The morphology of cataracts in HHCS seems to be similar in all cases. In the heterozygous G32C mutation, the age at onset of cataracts is very early. Greater awareness of this condition among ophthalmologists will lead to effective family counseling of those affected, by genetic testing or simple biochemical tests. Serum ferritin levels can be effectively used to screen for this condition in suspected families.

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

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.

Hereditary hyperferritinaemia???cataract syndrome: a challenging diagnosis for the hepatogastroenterologist

Hereditary hyperferritinaemia-cataract syndrome (HHCS) is a relatively rare disorder with an autosomal dominant trait. It can be caused by various mutations within the iron responsive element (IRE) of the L-ferritin gene. These mutations result in an increased translation of L-ferritin mRNA and consequently the accumulation of L-ferritin in different fluids and tissues. HHCS patients present with an isolated hyperferritinaemia in the absence of any sign of iron overload. Early onset bilateral cataract, probably due to accumulation of ferritin crystals in the lens, is the only presenting clinical manifestation. Internists, especially gastrohepatologists, should be aware of this syndrome and differentiate it from haemochromatosis which is much more frequent, in order to avoid unnecessary imaging procedures, liver biopsies and an eventual venesection therapy, which will only lead to microcytic anaemia. In the present paper we report the first cases with HHCS diagnosed in Belgium. At diagnosis, the seven known affected members of three different families had ferritin levels between 603 and 3432 microg/l (normal < 150 microg/l), and this in combination with normal iron and transferrin values. All of them were known with early-onset bilateral cataract and our postulated diagnosis of HHCS was confirmed after genetic sequencing of the L-ferritin gene, which showed a C39U point mutation in the first family, and an A40G point mutation in the IRE loop segment in the two other families. The other investigated members of the three families had normal ferritin values, no history of early-onset cataract and genetic analyses could not reveal a mutation in the IRE of their L-ferritin gene. In current clinical practice, gastroenterologists should remember that elevated ferritin levels in the absence of documented iron overload is not haemochromatosis.

Differential Degradation of Ferritin H- and L-Chains: Accumulation of L-Chain-Rich Ferritin in Lens Epithelial Cells

The storage of iron by ferritin is determined by tissue-specific composition of its 24 subunits, which are designated as either heavy (H) or light (L). For a better understanding of how lens epithelial cells regulate their ferritin subunit makeup, the degradation pattern of each subunit type was analyzed. In addition, age-related changes in ferritin concentration and subunit makeup were determined. Ferritin turnover in primary cultures of canine lens epithelial cells was determined by metabolic labeling with [(35)S]-methionine. Transient transfection with vectors containing coding sequences for either H- or L-chains were used to modify ferritin subunit makeup. Ferritin concentration was measured by ELISA. Immunodetection and fluorescence immunocytochemistry were used to study age-related changes in ferritin chain concentration. Inhibition of the proteasomal protein degradation pathway by clastolactacystin-beta-lactone had no effect on ferritin degradation, whereas inhibition of lysosomal degradation markedly increased ferritin levels, confirming that this system is involved in ferritin turnover. H-chain ferritin degraded at a faster rate than the L-chain. L-chain-rich ferritin in L-chain-transfected cells formed inclusion bodies that were localized to the cytosol. Similar inclusion bodies were found in older lens cells kept in cell culture for more than 8 days. Steady degradation of H-chain ferritin contributed to the maintenance of a constant level of this chain within the lens epithelial cells. In contrast, slower turnover of the L-chain resulted in accumulation of L-chain-enriched ferritin associated with cytoplasmic inclusion bodies. These L-chain-containing inclusion bodies were found in the cytosol of cells overexpressing L-ferritin chain and in nontransfected cells maintained in culture for 8 to 35 days. Overexpression of the L-chain has been associated with the formation of premature cataracts in humans with hereditary hyperferritinemia cataract syndrome. The formation of inclusion bodies in older lens epithelial cells, as demonstrated in the current investigation, is intriguing and could point to possible involvement of cytoplasmic L-chain-enriched ferritin aggregates in the formation of age-related cataract.

The Evaluation of Hyperferritinemia: An Updated Strategy Based on Advances in Detecting Genetic Abnormalities

The number of new genes implicated in iron metabolism has dramatically increased during the last few years. Alterations of these genes may cause hyperferritinemia associated or not with iron overload. Correct assignment of the specific disorder of iron metabolism requires the identification of the causative gene mutation. Here, we propose a rational strategy that allows targeting the gene(s) to be screened for a diagnostic purpose. This strategy relies on the age of onset of the disease, the type of clinical symptoms, the biochemical profile (elevated or normal serum transferrin saturation (TfSat)), the presence or not of visceral iron excess, and the mode of inheritance (autosomal recessive or dominant). Then, two main entities can be differentiated: genetic (adult or juvenile) hemochromatosis characterized by elevated TfSat, and hereditary hyperferritinemias where TfSat is normal (or only slightly modified). Adult genetic hemochromatosis (GH) is related mainly to mutations of the HFE gene, and exceptionally to mutations of the TFR2 gene. Juvenile GH is a rare condition related principally to mutations of the HJV gene coding for hemojuvelin, and rarely to mutations of the HAMP gene coding for hepcidin. Hereditary hyperferritinemias are linked to mutations of three genes: the L-ferritin gene responsible for the hereditary hyperferritinemia cataract syndrome (without iron overload), the ferroportin gene leading to a dominant form of iron overload, and the ceruloplasmin (CP) gene corresponding to an iron overload syndrome with neurological symptoms. The proposed strategic approach may change with the identification of other genes involved in iron metabolism.

A Point Mutation in the Iron-Responsive Element of the L-Ferritin in a Family with Hereditary Hyperferritinemia Cataract Syndrome

Hereditary hyperferritinemia cataract syndrome is an autosomal dominant condition that is characterized by a high serum ferritin level and bilateral early-onset cataracts in the absence of iron overload. The genetic abnormality is identified as a mutation in the 5' regulatory region of the L-ferritin messenger RNA known as the iron-responsive element (IRE). The IRE controls ferritin synthesis in response to cytoplasmic iron pools by interacting with regulatory proteins called iron responsive proteins. Mutations in the IRE decrease its affinity for iron responsive proteins, leading to the constitutive synthesis of L-ferritin which results in hyperferritinemia and the intracellular accumulation of ferritin in the lens and eventual cataract formation. A 22-year-old woman who was being investigated for hyperferritinemia was diagnosed with hereditary hyperferritinemia cataract syndrome after an extensive workup, including genetic testing for hemochromatosis and a liver biopsy to rule out iron overload. She developed anemia with phlebotomy treatments and subsequently developed symptomatic cataracts. The pedigree of her family affected with cataracts was consistent with an autosomal dominant transmission pattern. DNA was extracted from peripheral leukocytes of eight family members, four of whom were affected by cataracts. Polymerase chain reaction amplification of the 5' region of the L-ferritin gene was performed and a heterozygous point mutation (G32T) was identified in the bulge region of the IRE. The combination of early-onset cataracts and an elevated ferritin level should suggest this genetic syndrome.

Identification of a novel mutation in theL-ferritin IRE leading to hereditary hyperferritinemia-cataract syndrome

The hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare autosomal dominant disorder due to mutations affecting the iron responsive element (IRE) of the L-ferritin mRNA. We report on a new mutation, 43G > A, in the loop of the stem-loop structure of the L-ferritin IRE in the proband of a pedigree with early-onset bilateral cataracts.

Granulocyte function in patients with L-ferritin iron-responsive element (IRE) 39C-->T-positive hereditary hyperferritinaemia-cataract syndrome.

Hereditary hyperferritinaemia-cataract syndrome (HHCS) is an autosomal dominant trait associated with mutations in the iron responsive element (IRE) of the ferritin light-chain (L-ferritin) gene. Patients typically show elevated serum ferritin concentrations without iron overload and a bilateral cataract. Hyperferritinaemia can be associated with granulocyte dysfunction in patients with thalassemia beta and in haemodialysis patients. The effect of increased L-ferritin levels on granulocyte function in patients with HHCS is unknown. We examined glucose uptake, oxidative burst, chemotaxis, phagocytosis, apoptosis and intracellular calcium concentrations in polymorphonuclear leucocytes (PMNLs) of five affected members of a family with HHCS and in five healthy individuals matched for age and gender. Mutation testing revealed a 39C-->T transition in IRE in all five patients with HHCS. Serum ferritin levels of patients ranged between 907 and 2030 microg L(-1), respectively. In comparison with healthy individuals, PMNLs of patients with HHCS showed a significant increase in PMA-mediated stimulation of the oxidative burst, as well as a significantly higher stimulation of glucose uptake but no difference with respect to chemotaxis, phagocytosis, apoptosis and intracellular calcium concentrations. In summary, our study suggests that hyperferritinaemia in patients with IRE 39C-->T-positive HHCS is associated with activation of PMNLs but not with disturbance of fundamental PMNL function.

Clinical features and molecular analysis of seven British kindreds with hereditary hyperferritinaemia cataract syndrome.

Hereditary hyperferritinaemia cataract syndrome (HHCS) is an autosomal dominant disorder characterised by early onset cataracts and increased serum L-ferritin concentration. Affected individuals show nucleotide substitutions in the region of the L-ferritin gene (FTL) that encodes a regulatory sequence within the (mRNA)FTL termed the iron responsive element (IRE). We report the clinical features of seven HHCS kindreds containing 49 individuals with premature cataract. All the probands received diagnoses of HHCS after the incidental discovery of increased serum L-ferritin concentration (median 1420 microg/l; normal range 15-360 microg/l), in most cases during investigation or screening for anaemia. All the probands developed characteristic 'sunflower' morphology cataracts in childhood (median age at diagnosis 5 years), but had no other phenotypic features. All the affected kindreds showed nucleotide substitutions in FTL that were predicted to disrupt function of the (mRNA)FTL IRE. The severity of the clinical phenotype of HHCS was variable both within and between kindreds and showed no clear relationship to FTL genotype. HHCS should be included in the differential diagnosis of hyperferritinaemia and should be carefully distinguished from hereditary haemochromatosis. Measurement of the serum L-ferritin concentration should be included in the investigation of all individuals with early onset cataracts.

Hyperferritinaemia without iron overload: pathogenic and therapeutic implications.

It is not unusual to meet increased levels of ferritinaemia in patients apparently healthy. Among other causes of hyperferritinaemia, recently was described the Hereditary Hyperferritinemia Cataract Syndrome, a genetic condition characterized by increased serum ferritin values without iron overload and bilateral nuclear cataract, both of early onset. It has been demonstrated that single or double point mutations or deletions in the stem-loop structure of the iron regulatory element (I.R.E.) located in the 5 untranslated regions of the ferritin L-subunit gene (19q13.1) are responsible for the upregulation of ferritin. This overexpression only for the L-chain gives rise to typical piles in several tissues. When this altered ferritin accumulates in lens it causes bilateral nuclear cataracts, that is the peculiar sign of this syndrome. It is essential to differentiate true iron overload from Hereditary Hyperferritinaemia Cataract Syndrome (H.H.C.S.), because these patients rapidly develop iron deficient anaemia when venosectioned. Here we describe a case report about a 40 years old healthy female blood donor who presented isolated hyperferritinaemia without iron overload, in the absence of concomitant pathologies. Anamnestic, biochemical, instrumental and clinical investigations led us to diagnose H.H.C.S., a pathology first described in 1995. From 1995 to date about 40 cases concerning patients showing the characteristics of this syndrome from Europe, USA, and Australia were described. Biochemical, genetical and clinical investigations led finally to understand every matter of this pathology, providing conclusive and exhaustive explanations.

Hereditary hyperferritinemia-cataract syndrome: prevalence, lens morphology, spectrum of mutations, and clinical presentations.

To provide a comprehensive description of the clinical presentations, cataract morphology, and molecular basis of hereditary hyperferritinemia-cataract syndrome (HHCS) in 4 Australian pedigrees and to estimate its prevalence. All known cases of HHCS in southeastern Australia were ascertained. Family members provided a medical history and underwent physical examination, lens photography, and venipuncture for measurement of serum ferritin levels and DNA extraction. Sequence analysis of the iron-responsive element of the ferritin light chain on chromosome 19q13.3-qter was performed. We investigated 26 affected individuals from 5 Australian pedigrees. Two pedigrees with HHCS ascertained independently were subsequently found to form 1 large kindred carrying the mutation A40G. The minimum estimated prevalence of HHCS is 1/200000. One pedigree had the mutation G32C. Among 2 smaller pedigrees studied, one carried a novel mutation (C39A), and the other was identified through the 2-year-old propositus with cataract but no positive family history. The latter case was shown to be due to a de novo mutation (G32U). All cataracts were highly distinctive in morphology, consisting of slowly progressive flecks, vacuoles, and distinctive crystalline deposits scattered predominantly in the lens cortex but also in the nucleus. Eight of 18 affected individuals examined have required cataract extraction to date. No other identified clinical manifestations of HHCS were delineated. Cataract morphology in HHCS is highly distinctive. Longitudinal observation demonstrated slow progression of the cataracts. This study highlights that, although HHCS is an autosomal dominant condition, the diagnosis should be considered even in sporadic cataract of typical morphology. Furthermore, individuals with unexplained hyperferritinemia should be referred for ophthalmological assessment, as the cataract may be asymptomatic but lead to a correct diagnosis of HHCS. Clinical Relevance Progressive cataracts of highly distinctive morphology are an important feature of HHCS. Evaluation for this type of cataract may be of diagnostic value in patients with unexplained hyperferritinemia. Hereditary hyperferritinemia-cataract syndrome can be a cause of cataracts in pediatric patients even in the absence of any positive family history.

Identification of a Mechanism by Which Lens Epithelial Cells Limit Accumulation of Overexpressed Ferritin H-chain

The primary cultures of canine lens epithelial cells were transiently transfected with cDNAs for dog ferritin H- or L-chains in order to study differential expression of these chains. By using chain-specific antibodies, we determined that at 48 h after transfection overexpression of L-chain was much higher (9-fold over control) than that of H-chain (1.7-fold). We discovered that differentially transfected cells secrete overexpressed chains as homopolymeric ferritin into the media. Forty-eight hours after transfection accumulation of H-ferritin in the media was much higher (3-fold) than that of L-ferritin. This resulted in lowering of the concentration of H-chain in the cytosol. Co-transfection of cells with both H- and L-chain cDNAs increased the intracellular levels of H-chain and eliminated secretion of H-ferritin to the media. We concluded that lens epithelial cells differentially regulate concentration of both ferritin chains in the cytosol. The overexpressed L-chain accumulated in the cytosol as predominantly homopolymeric L-ferritin. This is in contrast to H-chain, which is removed to the media unless there is an L-chain available to form heteropolymeric ferritin. These data indicate that the inability of cells to more strictly control cytosolic levels of L-chain may augment its accumulation in lenses of humans with hereditary hyperferritinemia cataract syndrome, which is caused by overexpression of L-chain due to mutation in the regulatory element in the untranslated region of the mRNA of the chain.

Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations

AbstractUnexplained hyperferritinemia is a common clinical finding, even in asymptomatic persons. When early onset bilateral cataracts are also present, the hereditary hyperferritinemia-cataract syndrome (HHCS), because of heterozygous point mutation in the L ferritin iron-responsive element (IRE) sequence, can be suspected. We sequenced the L ferritin exon 1 in 52 DNA samples from patients referred to us for molecular diagnosis of HHCS. We identified 24 samples with a point mutation/deletion in the IRE. For the 28 samples in which no IRE mutation was present, we also genotyped HFE mutations and sequenced both H ferritin and ferroportin genes. We found an increased frequency of His63Asp heterozygotes (12 of 28) but no H ferritin mutations. We identified 3 new ferroportin mutations, producing, respectively, Asp157Gly, Gln182His, and Gly323Val amino acid replacements, suggesting that these patients have dominant type 4 hemochromatosis. This study demonstrates that both L ferritin IRE and ferroportin mutations can account for isolated hyperferritinemia. The presence of cataract does not permit the unambiguous identification of patients with HHCS, although the existence of a family history of cataract was only encountered in these patients. This raises the intriguing possibility that lens ferritin accumulation might be a factor contributing to age-related cataract in the general population. Additional causes of isolated hyperferritinemia remain to be identified.