Hereditary Hyperferritinemia Cataract Syndrome: Ferritin L Gene and Physiopathology behind the Disease—Report of New Cases

Abstract

Hereditary hyperferritinemia-cataract syndrome (HHCS) is a rare disease characterized by high serum ferritin levels, congenital bilateral cataracts, and the absence of tissue iron overload. This disorder is produced by mutations in the iron responsive element (IRE) located in the 5′ untranslated regions (UTR) of the light ferritin (FTL) gene. A canonical IRE is a mRNA structure that interacts with the iron regulatory proteins (IRP1 and IRP2) to post-transcriptionally regulate the expression of proteins related to iron metabolism. Ferritin L and H are the proteins responsible for iron storage and intracellular distribution. Mutations in the FTL IRE abrogate the interaction of FTL mRNA with the IRPs, and de-repress the expression of FTL protein. Subsequently, there is an overproduction of ferritin that accumulates in serum (hyperferritinemia) and excess ferritin precipitates in the lens, producing cataracts. To illustrate this disease, we report two new families affected with hereditary hyperferritinemia-cataract syndrome with previous known mutations. In the diagnosis of congenital bilateral cataracts, HHCS should be taken into consideration and, therefore, it is important to test serum ferritin levels in patients with cataracts.

Hereditary Hyperferritinemia-Cataract Syndrome in a Family With HFE-H63D Mutation

“…The CAGUGU sequence within the IRE is a non-coding sequence that is highly conserved, and this sequence was found to have an important role in IRP-IRE binding [9][10][11][12]. c.-160A>G mutation in this sequence was identified in 17 patients from six families from Kayseri and Nevşehir in Turkey and claimed to be the most prevalent mutation causing HHCS in Turkey [12].…”

Genetic predisposition to porto‐sinusoidal vascular disorder: A functional genomic‐based, multigenerational family study

“…Thus, mutations in highly conserved regions may have deleterious effects on these biological functions. For example, the substitution of adenine to guanine in CAGUGU, a highly conserved motif in the 5′‐untranslated region of the ferritin light chain results in hereditary hyperferritinemia‐cataract syndrome 23. This mutation prevents the formation of a crucial harpin which ensures the recognition and interaction between the RNA and the iron‐responsive element‐binding protein at low iron concentrations 23.…”

“…For example, the substitution of adenine to guanine in CAGUGU, a highly conserved motif in the 5′-untranslated region of the ferritin light chain results in hereditary hyperferritinemia-cataract syndrome. [23] This mutation prevents the formation of a crucial harpin which ensures the recognition and interaction between the RNA and the iron-responsive element-binding protein at low iron concentrations. [23] Similarly, our in silico FCHSD1_RNA structure analyses showed that the FCHSD1 R183W variant causes a change in both the secondary and tridimensional structures of FCHSD1_RNA.…”

“…[23] This mutation prevents the formation of a crucial harpin which ensures the recognition and interaction between the RNA and the iron-responsive element-binding protein at low iron concentrations. [23] Similarly, our in silico FCHSD1_RNA structure analyses showed that the FCHSD1 R183W variant causes a change in both the secondary and tridimensional structures of FCHSD1_RNA. Consequently, the mRNA folding may be altered, leading to an increase in its thermodynamic stability and eventually in its protein overproduction.…”

Structural and functional relationship of mammalian and nematode ferritins

“…The multiple functions of ferritin are evident by the binding of numerous transcription factors to the Fth1 gene promoter, e.g., activator protein 1 (AP-1 – involved in the regulation of cell growth, differentiation, and apoptosis), GATA-binding factor 1 (GATA-1 – involved in erythroid development), growth factor independent 1 transcriptional repressor (GFI1 – activated in hematopoiesis and oncogenesis), and HSF2 (promoting the expression of heat shock response genes) (based on www.genecards.org ). Mutations (e.g., deletions and single nucleotide polymorphisms (SNPs)) in 5′-UTR regions that disrupt the protein-promoter interactions in the IRE sites lead to the dysregulation of serum ferritin levels and the development of the hereditary hyperferritinemia cataract syndrome (Celma Nos et al, 2021 ). Recently, the regulation of ferritin chain translation independent of IRP-IRE has also been reported.…”