HGNC Approved Gene Symbol: FTL
SNOMEDCT: 699299001, 702398007;
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:48,965,309-48,966,879 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.33 | Hyperferritinemia-cataract syndrome | 600886 | Autosomal dominant | 3 |
| L-ferritin deficiency, dominant and recessive | 615604 | Autosomal dominant; Autosomal recessive | 3 | |
| Neurodegeneration with brain iron accumulation 3 | 606159 | Autosomal dominant | 3 |
The iron storage protein ferritin is a complex of 24 L-ferritin (FTL) and H-ferritin (FTH1; 134770) subunits in ratios that vary in different cell types. FTH subunits exhibit ferroxidase activity, converting Fe(2+) to Fe(3+), so that iron may be stored in the ferritin mineral core, which prevents undesirable reactions of Fe(2+) with oxygen. FTL subunits are devoid of catalytic activity but are thought to facilitate nucleation and mineralization of the iron center (summary by Sammarco et al., 2008).
Studies of ferritin synthesis in cell-free systems by Watanabe and Drysdale (1981) suggested that the H and L subunits in human and rat are derived from different mRNA molecules.
Brown et al. (1983) noted that mammalian liver and spleen ferritin (relative mass about 450 kD) consists of 24 subunits of 2 species, the heavy subunit (relative mass, 21 kD) and the light subunit (relative mass, 19 kD). They presented evidence that, in rat, the 2 subunits are coded by separate mRNAs and that a family of genes encodes the light subunit.
Cazzola et al. (1997) stated that the human ferritin L chain contains 174 residues and has an apparent molecular mass of 19 kD. They found that serum ferritin, with an apparent molecular mass of 23 kD, was a glycosylated form of intracellular ferritin L chain.
Curtis et al. (2001) reported that the human ferritin light chain contains 175 residues and that the peptide folds into 5 alpha-helical domains designated A through E.
By study of human/Chinese hamster hybrid cells and use of a radioimmunoassay specific for human ferritin, Caskey et al. (1983) showed that chromosome 19 encodes the structural gene for ferritin. By in situ hybridization, McGill et al. (1984) confirmed the assignment of the light chain gene to chromosome 19 but concluded that the heavy chain is encoded by 1p. By study of hamster-human and mouse-human hybrid cells, some with translocations involving chromosome 19, Worwood et al. (1985) concluded that light subunits of ferritin (rich in human spleen ferritin) are coded by a gene in segment 19q13.3-qter and that the gene for the heavy subunit (rich in human heart ferritin) is located on chromosome 11. By miniaturized restriction enzyme analysis of sorted chromosomes, Lebo et al. (1985) demonstrated ferritin light-chain genes on at least 3 chromosomes.
Munro et al. (1988) reviewed information on the ferritin genes. They pointed out that in both the rat and the human, several ferritin pseudogenes can be recognized not only because they are flanked by 5-prime and 3-prime direct repeats representing the site of their retroinsertion into the chromatin, but also because they differ from functional genes by the absence of introns and by the presence of polyadenylic acid tails that have been inserted onto the 3-prime end of the messenger transcription of the functional gene. They cited the evidence of Santoro et al. (1986) and of Hentze et al. (1986) that there is only one expressed H and one expressed L gene in the human genome.
By typing the progeny of 2 sets of genetic crosses, Filie et al. (1998) determined the map location of loci containing sequences related to the ferritin light chain gene in the mouse. Twelve loci were positioned on 11 different chromosomes. One of these genes mapped to a position on chromosome 7 predicted to contain the expressed Flt1 gene on the basis of the previously determined position of the human homolog on 19q13.3-q13.4.
Human ferritins expressed in yeast normally contain little iron, which led Shi et al. (2008) to hypothesize that yeast, which do not express ferritins, might also lack the requisite iron chaperones needed for delivery of iron to ferritin. In a genetic screen to identify human genes that, when expressed in yeast, could increase the amount of iron loaded into ferritin, Shi et al. (2008) identified poly(rC) binding protein-1 (PCBP1; 601209). PCBP1 bound to ferritin in vivo, and bound iron and facilitated iron loading into ferritin in vitro. Depletion of PCBP1 in human cells inhibited ferritin iron loading and increased cytosolic iron pools. Thus, Shi et al. (2008) concluded that PCBP1 can function as a cytosolic iron chaperone in the delivery of iron to ferritin.
Using reporter genes expressed in HEK293 cells, Sammarco et al. (2008) determined that expression of both FTL and FTH increased in the presence of excess iron under normoxic culture conditions (20% oxygen). However, expression of FTL, but not FTH, increased in the presence of excess iron under hypoxic culture conditions (1% oxygen). Sammarco et al. (2008) concluded that expression of FTL and FTH are differentially regulated.
Mancias et al. (2014) used quantitative proteomics to identify a cohort of novel and known autophagosome-enriched proteins, including cargo receptors, in human cells. Like known cargo receptors, nuclear receptor coactivator-4 (NCOA4; 601984) was highly enriched in autophagosomes, and associated with autophagy-8 (ATG8)-related proteins that recruit cargo-receptor complexes into autophagosomes (see, e.g., GABARAPL2, 607452). Unbiased identification of NCOA4-associated proteins revealed ferritin heavy chain (see FTH1, 134770) and FTL, components of an iron-filled cage structure that protects cells from reactive iron species but is degraded via autophagy to release iron. Mancias et al. (2014) found that delivery of ferritin to lysosomes required NCOA4, and an inability of NCOA4-deficient cells to degrade ferritin led to decreased bioavailable intracellular iron. Mancias et al. (2014) concluded that their work identified NCOA4 as a selective cargo receptor for autophagic turnover of ferritin (ferritinophagy), which is critical for iron homeostasis, and provided a resource for further dissection of autophagosomal cargo-receptor connectivity.
Hyperferritinemia with or without Cataract
Beaumont et al. (1995) identified a mutation in the iron-responsive element (IRE) in the 5-prime noncoding region of the FTL gene (134790.0001) in the hyperferritinemia-cataract syndrome (HRFTC; 600886).
Camaschella et al. (2000) reported a father and daughter with only modest hyperferritinemia and subclinical cataract in whom they identified a mutation in the IRE of FTL (51G-C; 134790.0009).
In 17 unrelated patients with hyperferritinemia, 1 of whom had bilateral cataract, Kannengiesser et al. (2009) identified heterozygosity for a missense mutation in the FTL N terminus (T30I; 134790.0017).
Neurodegeneration with Brain Iron Accumulation 3
Curtis et al. (2001) identified an adenine insertion after nucleotide 460 of the FTL gene (134790.0010) that is predicted to alter C-terminal residues of the FTL gene product in patients with neurodegeneration with brain iron accumulation-3 (NBIA3; 606159), also known as neuroferritinopathy.
L-ferritin Deficiency
In a healthy 52-year-old woman with low serum L-ferritin (LFTD; 615604), Cremonesi et al. (2004) identified a heterozygous mutation in the ATG start codon of the FTL gene (M1V; 134790.0018), predicted to disable protein translation and expression. The findings suggested that L-ferritin has no effect on systemic iron metabolism, and suggested that haploinsufficiency of L-ferritin does not cause neurologic or hematologic clinical effects.
In a 23-year-old woman with autosomal recessive serum L-ferritin deficiency, Cozzi et al. (2013) identified a homozygous truncating mutation in the FTL gene (E104X; 134790.0019). The FTL gene was chosen for sequencing because the patient had undetectable serum ferritin levels. The patient had childhood generalized epilepsy, mild cognitive impairment, alopecia, and restless legs syndrome, but no hematologic abnormalities. Cozzi et al. (2013) stated that this was the first patient reported with complete loss of FTL.
The phenotype resulting from FTL mutations depends on the location of the mutation(s) within the FTL gene. In patients with the hyperferritinemia-cataract syndrome, mutations most commonly occur within the iron-response element (IRE) stem loop of the FTL mRNA, resulting in decreased affinity for iron-response protein binding and overproduction of FTL protein. This excess ferritin aggregates in the ocular lens. Patients with neurodegeneration with brain iron accumulation-3 have truncating mutations in exon 4 of the FTL gene, resulting in frameshifts and accumulation of ferritin-containing spherical inclusions in the brain and other organs. One control individual with haploinsufficiency of the FTL gene had low levels of serum ferritin, but no hematologic or neurologic abnormalities, indicating that haploinsufficiency of FTL is not pathogenic (Cremonesi et al., 2004). Finally, 1 patient with childhood idiopathic generalized epilepsy, mild neurocognitive impairment, and restless legs syndrome has been reported to have complete loss of FTL; this patient had no hematologic abnormalities (summary by Cozzi et al., 2013).
Vidal et al. (2008) found that transgenic mice expressing human FTL with the 498insTC mutation (134790.0014) developed histologic and behavioral features that mimicked human hereditary ferritinopathy. Expression of the transgene caused behavioral and motor dysfunction, leading to shorter life span. Histologic and immunohistochemical analysis revealed that, by 8 weeks of age, transgenic mice developed nuclear and intracytoplasmic inclusions in neurons and glia throughout the central nervous system and in postmitotic cells in most peripheral tissues. Nuclear inclusions were made up of accumulated ferric iron, detergent-insoluble ferritin, ubiquitinated proteins, and elements of the proteasome. Nuclear inclusions became enlarged and almost completely occupied the nucleus, displacing chromatin up against the nuclear membrane.
This mutation, previously designated here as c.-146A-G, is now referred to as c.-160A-G (+40A-G) (Luscieti et al., 2013).
Beaumont et al. (1995) demonstrated that affected members of a 3-generation family with autosomal dominant hyperferritinemia and cataract (HRFTC; 600886) carried a heterozygous A-to-G transition in the iron-responsive element (IRE) of the FTL gene. The authors referred to the variant as 40A-G. Affected members presented with early-onset bilateral cataract. Slit-lamp examination demonstrated deposits of dust-like spots (pulverulent cataract) in all layers of both lens. There were no other clinical manifestations. All affected members had an elevated level of circulating ferritin with no other hematologic or biochemical abnormalities. Genetic hemochromatosis was excluded by liver biopsy which showed no iron overload but a heavy deposit of lipofuscin pigment in hepatocytes thought to be due to the accumulation of L ferritin. Affected members of the family had an A-to-G transition in the highly conserved CAGUGU motif that constitutes the IRE loop and mediates the high-affinity interaction with the iron regulatory protein (100880). They showed that the mutation abolished the finding of IRP in vitro and leads to a high constitutive, poorly regulated L ferritin synthesis in cultured lymphoblastoid cells established from affected patients.
Aguilar-Martinez et al. (1996) identified an A-to-G transition at position 146 of the FTL gene in heterozygous state in an 8-year-old boy and his father, both of whom had hyperferritinemia and cataract. The paternal grandfather also suffered from cataract. Both parents were of French origin. The mother had normal ferritin levels and no cataract. Both this and the 147G-C mutation (134790.0002) involved the 5-base sequence (CAGUG) that characterizes the loop structure of the IRE. (This A-to-G mutation appears to be the same as the A-to-G mutation reported by Beaumont et al. (1995) since the IRE contains only 1 adenine residue.)
In a large kindred in which 11 members had hyperferritinemia-cataract syndrome, McLeod et al. (2002) identified the same mutation in the conserved CAGUG motif. They referred to the mutation as an A-to-G change at nucleotide 40.
This mutation, previously designated here as c.-147G-C, is now referred to as c.-159G-C (+41G-C) (Luscieti et al., 2013).
In 1 of 2 families with hereditary hyperferritinemia-cataract syndrome (HRFTC; 600886) described by Girelli et al. (1995), Girelli et al. (1995) found a G-to-C transversion in the third nucleotide of the CAGUG sequence in the IRE of the FTL gene. The father and 2 children were affected. Different from hereditary hemochromatosis patients, they had normal to low serum iron and transferrin saturation, and no evidence of parenchymal iron overload as assessed by liver and bone marrow biopsy. When unnecessary phlebotomies were performed, they rapidly developed iron-deficient anemia (reversed by adequate iron therapy), with persistently elevated levels of serum ferritin. The dominant inheritance and the lack of relation with HLA were further differences from hereditary hemochromatosis. Aguilar-Martinez et al. (1996) stated that this mutation was located at nucleotide 147 in the 5-prime untranslated portion of the FTL gene sequence.
Luscieti et al. (2013) referred to this mutation as c.-168G-A (+32G-A).
Cazzola et al. (1997) studied 2 families with hyperferritinemia and congenital cataract (HRFTC; 600886) in multiple generations in an autosomal dominant pedigree pattern. In 1 family, hereditary hemochromatosis was incorrectly diagnosed on the basis of hyperferritinemia; microcytic anemia and low serum iron developed after venesections were instituted, whereas serum ferritin levels did not change significantly. It appeared to these investigators that ferritin L-subunit synthesis was dysregulated in affected individuals. They postulated that the L-subunit gene iron-responsive element of affected individuals had a molecular lesion preventing high-affinity for an iron regulatory protein (IRP) binding and leading to overproduction of L subunits. Four affected members of family 1 were heterozygous for a point mutation in the IRE of the L-subunit: a single G-to-A transversion at nucleotide 32 in the highly conserved, 3-nucleotide motif forming the IRE bulge.
Shekunov et al. (2011) reported the 32G-A mutation in 13 members of a 5-generation Midwestern American family of German ancestry. Of these 13 members, 9 had astigmatism of greater than 1 diopter, an association not previously reported in hyperferritinemia and congenital cataract. Compared to the 32G-T mutation (134790.0006) reported in another family in the report, higher ferritin levels and more severe cataracts were associated with mutation 32G-A.
Luscieti et al. (2013) referred to these mutations as c.-182C-T (+18C-U) and c.-178T-G (+22U-G).
In a family with hyperferritinemia and cataract (HRFTC; 600886), Cazzola et al. (1997) found that affected members had 2 mutations on 1 allele of the FTL gene; these were stated as a 18C-U change and a 22U-G change in the lower stem of the IRE of the ferritin L-subunit gene. The proband, a 26-year-old woman, was suspected of having hereditary hyperferritinemia with congenital cataract because of a high serum ferritin with normal blood cell counts and normal serum iron and transferrin saturation. The woman had asymptomatic congenital nuclear cataract as did 2 other affected members of this pedigree, her sister and her maternal grandfather.
Luscieti et al. (2013) referred to this mutation as c.-190_-162del29 (+10_38del29).
In a family with individuals in 3 generations affected by hyperferritinemia-cataract syndrome (HRFTC; 600886), Girelli et al. (1997) demonstrated that the syndrome was produced by a 29-bp deletion in the IRE of the FTL gene. The deletion involved the entire 5-prime sequence essential to base pairing of the IRE stem and was predicted to cause the disruption of IRE stem-loop secondary structure and the nearly complete abolition of the negative control of ferritin synthesis by IRE/IRP binding. Girelli et al. (2001) provided a follow-up of this family with affected members in 4 generations in an autosomal dominant pattern. Slit-lamp photographs of the lens taken a few days before cataract surgery showed a pulverulent cataract in an 11-year-old member of the family and a sunflower cataract in his 31-year-old aunt.
Luscieti et al. (2013) referred to this mutation as c.-168G-T (+32G-U).
Martin et al. (1998) described 2 families with hyperferritinemia-cataract syndrome (HRFTC; 600886) with a novel mutation in the bulge of the IRE stem of the FTL gene and showed that this mutation alters the protein-binding affinity of the IRE in vitro to the same extent as the 2 mutations that alter adjacent nucleotides in the IRE loop, 146A-G (134790.0001) and 147G-C (134790.0002). They found that some variability in the age of onset of cataract can be associated with this disorder, probably because of additional genetic or environmental factors that modulate the penetrance of the FTL defect in the lens. They confirmed that the patients did not have increased iron stores despite the persistence of elevated serum ferritin levels and that, accordingly, they do not tolerate venesection therapy well. In the 2 families, affected members were heterozygous for a G-to-T transition in the bulge of the IRE. The mutation abrogated the basepairing between G32 and C50, which might be necessary for the proper conformation of the IRE.
Shekunov et al. (2011) reported the 32G-T mutation in a 5-generation Midwestern American family of British and German/Austrian ancestry. Nine affected members also had astigmatism of greater than 1 diopter, an association not previously reported in hyperferritinemia-cataract syndrome.
Luscieti et al. (2013) referred to this mutation as c.-161C-T (+39C-U).
Mumford et al. (1998) described mutations in 2 English families with hereditary hyperferritinemia-cataract syndrome (HRFTC; 600886). The proband of one family was heterozygous for a point mutation that corresponded to a +39 C-to-U substitution in the L-ferritin mRNA. The second family carried a heterozygous point mutation corresponding to a +36 C-to-A transversion in the L-ferritin mRNA (134790.0008). The proband in the latter family was investigated for anemia, detected at one of her regular sessions to give blood for transfusion. She had had surgical extraction of premature cataracts, as had 8 other family members. Her son required cataract extraction at 5 years of age.
McLeod et al. (2002) identified the same mutation in affected members of an Australian family originating from Italy. The proband was a 45-year-old man with a history of bilateral cataracts and hyperferritinemia in the absence of iron overload. His 11-year-old son had been followed for congenital cataracts since the age of 5 years.
Luscieti et al. (2013) referred to this mutation as c.-164C-A (+36C-A).
Mumford et al. (1998) described mutations in 2 English families with hereditary hyperferritinemia-cataract syndrome (HRFTC; 600886). The proband of one family was heterozygous for a point mutation that corresponded to a +39 C-to-U substitution (134790.0007) in the L-ferritin mRNA. The second family carried a heterozygous point mutation corresponding to a +36 C-to-A transversion in the L-ferritin mRNA. The proband in the latter family was investigated for anemia, detected at one of her regular sessions to give blood for transfusion. She had had surgical extraction of premature cataracts, as had 8 other family members. Her son required cataract extraction at 5 years of age.
Luscieti et al. (2013) referred to this mutation as c.-149G-C (+51G-C).
In 2 members of a Canadian family with moderate increase in serum ferritin and clinically silent bilateral cataract (HRFTC; 600886), Camaschella et al. (2000) identified a 51G-C mutation in the IRE of the FTL gene. Father and daughter were affected. In this instance, binding of the mutated IRE to iron regulatory proteins was reduced, compared with wildtype. Structural modeling predicted that 51G-C induces a rearrangement of basepairing at the lateral bulge of the IRE structure that is likely to modify IRE conformation. Of significance is the fact that cataracts were asymptomatic in both the father and the 15-year-old daughter.
Giansily-Blaizot et al. (2013) reported a 54-year-old woman of Canadian descent with hyperferritinemia and cataracts who was found to carry a homozygous +51G-C mutation in the FTL gene. Several family members, including both possibly consanguineous parents and 2 sibs, had visual impairment or known cataracts, but these individuals were not available for examination. Homozygous mutations are very unusual in this disorder, but the patient's phenotype was similar to that of heterozygous mutation carriers. Giansily-Blaizot et al. (2013) speculated that the mutation, which does not occur at the highly conserved region in the bulge or upper stem of the iron response element of the FTL gene, may have milder effects than other mutations, even in the homozygous state.
In a large family segregating an autosomal dominant basal ganglia disease, known as neurodegeneration with brain iron accumulation-3 or neuroferritinopathy (NBIA3; 606159), and in 5 additional individuals with similar manifestations, Curtis et al. (2001) identified an adenine insertion after nucleotide 460 of the FTL gene, which was predicted to alter the 22 C-terminal residues of the gene product and extend the chain by 4 additional residues. The mutation is predicted to disrupt the end of the D helix, the DE loop, and the E helix. Residues of the E helix form hydrophobic channels in the ferritin 4-fold axes of symmetry, are highly conserved, and are essential for iron core formation. This mutation was not identified in over 300 Cumbrian controls.
Although Chinnery et al. (2003) reported that they identified the 460insA mutation in affected members of a French family with neuroferritinopathy, Devos et al. (2009) concluded that the mutation in that family was actually a 458insA change (134790.0016). Both mutations create the same EcoN1 restriction site.
Luscieti et al. (2013) referred to this mutation as c.-178_-173del6 (+22_27del6).
Cazzola et al. (2002) described an Italian family in which elevated serum ferritin and early-onset severe bilateral cataract (HRFTC; 600886) were associated with a 6-bp deletion in the iron-responsive element of the FTL gene. The deletion occurred in a TCT repetition and may have occurred through a mechanism of slippage mispairing. The mutation could be interpreted as deletion 22-27, 23-28, 24-29, or 25-30.
Luscieti et al. (2013) referred to this mutation as c.-168G-C (+32G-C).
In affected members of a family with hyperferritinemia-cataract syndrome (HRFTC; 600886), Campagnoli et al. (2002) identified a heterozygous 32G-C transversion in the FTL gene. The authors noted that 2 other mutations had been described at nucleotide 32 (32G-A; 134790.0003 and 32G-T; 134790.0006), which is in the IRE bulge structure. Two sisters in the last generation of the family developed cataracts at age 18 months, earlier than most reported cases.
In a 19-year-old man with parkinsonism, ataxia, and corticospinal signs consistent with neuroferritinopathy (NBIA3; 606159), Maciel et al. (2005) identified a heterozygous 474G-A transition in the FTL gene, resulting in an ala96-to-thr (A96T) substitution in a conserved residue of the protein. His asymptomatic mother and 13-year-old brother also carried the mutation. MRI showed bilateral pallidal necrosis in the patient and his mother, and all 3 mutation carriers had decreased serum ferritin. The patient also had mild nonprogressive cognitive deficit and episodic psychosis, which may have been unrelated since a noncarrying uncle had schizophrenia.
In affected members of a large French family with neuroferritinopathy (NBIA3; 606159), Vidal et al. (2004) identified a heterozygous 2-bp insertion (498_499insTC) in exon 4 of the FTL gene, resulting in the addition of 16 residues at the C terminus predicted to cause loss of the C-terminal secondary structure. The phenotype was characterized by onset in the third decade of progressive parkinsonism, cerebellar ataxia, pyramidal signs, and cognitive decline. Neuropathologic analysis showed ferritin-containing inclusion bodies in neurons and glia throughout the brain, as well as in some extraneuronal tissues. Vidal et al. (2004) noted that the findings were consistent with a hypothesis that mutant FTL may not be able to store iron appropriately, causing an accumulation of intracellular iron and mutant FTL polypeptides.
In a Japanese mother and son with neuroferritinopathy (NBIA3; 606159), Ohta et al. (2008) identified a heterozygous 16-bp duplication (469_484dup) in exon 4 of the FTL gene, resulting in the replacement of the 14 C-terminal residues with a novel 23-amino acid sequence. The son developed hand tremors in his mid-teens and foot dragging at age 35. By age 42, he had generalized hypotonia, hyperextensibility, unsteady gait, aphonia, micrographia, hyperreflexia, and cognitive impairment. Rigidity, spasticity, dystonia, an chorea were not observed. His mother had hand tremors at age 10 and difficulty walking at age 35, developed cognitive impairment and akinetic mutism, and died at age 64. Brain imaging in both patients showed symmetric cystic changes in the basal ganglia. The son had hyperintense lesions in the basal ganglia and substantia nigra on MRI. Ohta et al. (2008) suggested that the mutant FTL protein was unable to retain iron, which was released in the nervous system, causing oxidative damage.
In affected members of a French family with neuroferritinopathy (NBIA3; 606159), Devos et al. (2009) identified a 1-bp duplication (458dupA) in the FTL gene. The patients developed symptoms between 24 and 44 years of age. Presenting features included dystonia, causing writing difficulties or a gait disorder, followed by rapid progression to orofacial, pharyngeal, and laryngeal dystonia. L-DOPA was not effective. None developed spasticity, abnormal reflexes, or marked tremor. Three deceased family members developed cerebellar ataxia. All developed a moderate subcortical/frontal dementia. Other atypical features included a limitation of vertical eye movements and mild dysautonomia, including orthostatic hypotension, constipation, and urinary incontinence. Brain imaging showed iron deposition and cystic cavitation of the basal ganglia. Serum ferritin levels were decreased. The family had originally been thought to carry a different FTL mutation (460insA; 134790.0010) (Chinnery et al., 2003).
In 17 unrelated patients with hyperferritinemia (HRFTC; 600886), 1 of whom had bilateral cataract, Kannengiesser et al. (2009) identified heterozygosity for an 89C-T transition in the FTL gene, resulting in a thr30-to-ile (T30I) substitution at a highly conserved residue in the N-terminal 'A' alpha helix. Cosegregation analysis in 10 families carrying the T30I mutation showed that the mutation was present in 20 affected relatives but was absent in 10 relatives with normal serum ferritin levels; the mutation was also absent in 528 control individuals. There were significant fluctuations in serum ferritin levels, both over time in a given individual and between affected individuals within the same family. No characteristic clinical symptoms were found in the 37 affected individuals carrying the mutation, although 4 complained of joint pain and 3 of asthenia. Serum ferritin hyperglycosylation ranging from 90 to 99% (normal range, 50 to 80%) was observed in 9 mutation-positive individuals tested. Kannengiesser et al. (2009) hypothesized that the mutation might increase the efficacy of L-ferritin secretion by increasing the hydrophobicity of the N-terminal 'A' alpha helix.
In a 52-year-old woman with decreased serum L-ferritin (LFTD; 615604), Cremonesi et al. (2004) identified a heterozygous c.1A-G transition in the initiation codon of the FTL gene, resulting in a met1-to-val (M1V) substitution. The mutation was predicted to disable protein translation and expression. The woman was a control subject in a genetic study of hyperferritinemia-cataract syndrome and had no history of iron deficiency anemia or neurologic dysfunction. These findings suggested that L-ferritin has no effect on systemic iron metabolism, and also indicated that haploinsufficiency of L-ferritin does not cause clinical hematologic or neurologic abnormalities.
In a 23-year-old Italian woman with serum L-ferritin deficiency (LFTD; 615604), Cozzi et al. (2013) identified a homozygous c.310G-T transversion in exon 3 of the FTL gene, resulting in a glu104-to-ter (E104X) substitution in the middle of alpha-helix C, resulting in a truncated protein unable to fold into a full ferritin cage. The FTL gene was chosen for sequencing because the patient had undetectable serum levels of ferritin. There was no FTL protein in patient fibroblasts, although mRNA levels were similar to controls. The patient had childhood idiopathic generalized epilepsy that later resolved, mild cognitive impairment, and restless legs syndrome. Patient cells showed normal FTH (134770) expression, with increased iron incorporation into H homopolymer ferritin compared to controls. This was associated with a 4-fold decrease of the labile iron pool in patient cells. Expression of wildtype FTL ameliorated these cellular defects. E104X fibroblasts showed additional abnormalities, including increased turnover of H homopolymer ferritin and increased production of reactive oxygen species, as well as increased cellular toxicity compared to controls. Reprogrammed neurons from patient fibroblasts also showed increased reactive oxygen species as well as iron deficiency. Cozzi et al. (2013) stated that this was the first patient reported with complete loss of FTL, but noted that the phenotype could result either from a loss of FTL function or a gain of function via altered activity of the FTH homopolymer.
In affected members of a Spanish family with hyperferritinemia with or without cataract (HRFTC; 600886), Luscieti et al. (2013) identified a c.-164C-T transition in the FTL gene, resulting in a +36C-U change in the upper stem of the IRE. In vitro studies showed that the mutation caused a mild reduction in the binding of iron regulatory proteins. The proband, who was born of consanguineous parents, was a 54-year-old woman with a 10-year history of hyperferritinemia and cataracts since 18 years of age. She had no signs of iron overload; serum iron, transferrin saturation, and liver functional tests were normal. A sister and cousin had a similar disorder. Family history revealed an affected deceased uncle and an affected deceased father. The proband's deceased mother was never diagnosed with cataracts, but had severe myopia. Three children of the proband and her sister also showed signs of the disorder. The proband and her sister were found to be homozygous for the mutation, whereas the affected children and the cousin were heterozygous for the mutation. The individuals with the homozygous mutations were not significantly more affected than heterozygotes. The report indicated that genotype/phenotype correlations in this disorder are difficult to establish due to inter- and intraindividual variability.
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