A family with hereditary hyperferritinaemia cataract syndrome: evidence of incomplete penetrance and clinical heterogeneity

Ferritin, the major intracellular iron store protein, consists of 24 subunits of two types, H (heavy) and L (light) encoded in chromosomes 11 and 19, respectively (Worwood, 1982). Ferritin synthesis is regulated by iron intracellular levels; when the supply of iron to the cell is limited, ferritin translation is inhibited, conversely, when cellular iron is abundant ferritin synthesis takes place. The binding of the 5′ untranslated region (5′-UTR) of FTL mRNA to trans-acting iron regulatory proteins (IRPs) prevents the binding of the translation initiation complex and thus blocks translation of the ferritin protein (Muckenthaler et al, 1998). Mutations in the 5′UTR of the FTL gene produce elevated serum ferritin and clinically result in hereditary hyperferritinaemia cataract syndrome (HHCS), an autosomal dominant disease characterized by early onset bilateral cataract. The present study analyzed a family with bilateral cataract and marked hyperferritinaemia. Genomic DNA was isolated from peripheral blood with conventional methods and the FTL gene, including IRE (Iron Regulatory Element) region, was amplified as described elsewhere (Allerson et al, 1999). DNA sequencing analysis was performed in ABI PRISM 310 genetic analyzer (Applied Biosystems, Foster City, CA) according supplier’s conditions. The family with hyperferitinaemia was detected through a one-year screening programme of patients with early onset cataract (50 non-related patients or families). All assays were performed two times with a normal control included. Clinical characteristics of lens opacities were analyzed through slit-lamp. The affected family was referred to the General Hospital of Mexico. The protocol was approved by the Ethics Committee and patients gave informed consent to the study. We analyzed a three-generation Mexican family segregating autosomal dominant cataract that included 11 affected patients and nine unaffected subjects. Except for patient III-2, who presented strabismus, no other systemic or ocular anomalies were present. Hyperferritinaemia was confirmed in all affected members of the family with cataract and in one member with no lens opacity (III-4). The pedigree and morphology of cataracts of the family are shown in Fig 1. The onset of cataract symptoms in the propositus (IV-1) occurred at 10 years of age with diminution of visual acuty (VA). He underwent surgery when 25-years-old. His sibling (IV-2) presented diminution of VA at 6–8 years old and underwent surgery at 22 years. Patient III-4, carefully examined, had a child (IV-4) with HHCS and his mother (II-4) underwent surgery for lens opacities that were probably secondary to HHCS, when aged 50 years. DNA analysis of the affected members with cataract and of patient III-4 (except deceased members) detected a mutation in the lower stem of the IRE region of the FTL gene, in which adenine was substituted for cytosine at position +50 (Fig 2). These data indicate that the absence of cataract in Patient III-4 was due to incomplete penetrance of HHCS. The C50A change was absent in unaffected members of the family and 100 normal controls which excluded it as a neutral polymorphism. Pedigree of the family. A four-generation pedigree segregating hereditary hyperferritinaemia cataract syndrome. Squares and circles symbolize males and females, respectively, and black symbols denote affected patients with cataract. Levels of serum ferritin, age of onset (O) and age at surgery (S) are shown besides each affected patient with HHCS. y, years; NB, new born; mo, months. DNA sequencing analysis and predicted IRE structures of wild-type (WT) and C50A mutant FTL mRNAs, computed on the RNA mfold server. Arrows indicate the position of the mutation that appears to alter the bulge, with a rearrangement of base pairing expected to modify the conformation of the lower stem. The nucleotide substitution +50 detected in our family is in the opposite nucleotide to that reported in the +32 nucleotide (Addess et al, 1997). It has been shown that the unpaired cytosine-guanine (+32 and +50) adopts an extrahelical conformation and is structurally dynamic; the tendency of an unpaired nucleotide to stack within the helix is dependent upon the sequence of adjacent base pairs (Bhattacharyya et al, 1990). The mutation reported here is located close to another, different mutation (+51) previously reported in a Canadian family (Camaschella et al, 2000). In this case, G51C substitution induces a significant rearrangement of base pairing at the lateral bulge of IRE structure. In our family, computation analysis of mRNA folding of the first 75 nucleotides of FTL mRNA (Mathews et al, 2004) predicted that the C50A transversion induces a significant modification that appears to alter the bulge, with a rearrangement of base pairing expected to modify the conformation of the lower stem (Fig 2). Some HHCS mutations might also act by disrupting important secondary structural elements of the IRE region of the FTL gene, including the A-form helix of the lower stem, the extra-helical conformation of the bulged cytosine, the A-form helical conformation of the upper stem, the intraloop base pair, and the base-stacking interactions within the loop (Allerson et al, 1999). Mutations in the lower stem of the IRE region of the FTL gene result in different phenotypes (Lachlan et al, 2004); our family presented different phenotypes with several degrees of affection, different levels of serum ferritin and different age of onset. It has been proposed that mutations affecting the lower part of the IRE structure determine lower levels of serum ferritin (Cazzola et al, 1997); our findings showed that mutations in this region also produce high levels of serum ferritin. In conclusion, we have characterized a novel mutation located at the IRE sequence of the FTL gene. Interestingly, Patient III-4, who had hyperferritinaemia and C50A mutation showed no visual acuity impairment and no lens opacities but his child presented with congenital cataract due to HHCS that required surgery within the first months of life. Thus, apart from the gene mutation, other genetic, epigenetic or environmental factors must play a significant role in disease manifestation.

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