Cited by 47Iron Metabolism and DisordersNeurological diseases and metabolismRestless Legs Syndrome Research

Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome

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Cozzi, Anna, Santambrogio, Paolo, Privitera, Daniela, Broccoli, Vania, Rotundo, Luisa Ida, Garavaglia, Barbara, Benz, Rudolf, Altamura, Sandro +3 more·2013·Journal of Experimental Medicine

Abstract

The ubiquitously expressed iron storage protein ferritin plays a central role in maintaining cellular iron homeostasis. Cytosolic ferritins are composed of heavy (H) and light (L) subunits that co-assemble into a hollow spherical shell with an internal cavity where iron is stored. The ferroxidase activity of the ferritin H chain is critical to store iron in its Fe3+ oxidation state, while the L chain shows iron nucleation properties. We describe a unique case of a 23-yr-old female patient affected by a homozygous loss of function mutation in the L-ferritin gene, idiopathic generalized seizures, and atypical restless leg syndrome (RLS). We show that L chain ferritin is undetectable in primary fibroblasts from the patient, and thus ferritin consists only of H chains. Increased iron incorporation into the FtH homopolymer leads to reduced cellular iron availability, diminished levels of cytosolic catalase, SOD1 protein levels, enhanced ROS production and higher levels of oxidized proteins. Importantly, key phenotypic features observed in fibroblasts are also mirrored in reprogrammed neurons from the patient’s fibroblasts. Our results demonstrate for the first time the pathophysiological consequences of L-ferritin deficiency in a human and help to define the concept for a new disease entity hallmarked by idiopathic generalized seizure and atypical RLS.

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Authors
Cozzi, A., Santambrogio, P., Privitera, D., Broccoli, V., Rotundo, L. I., Garavaglia, B., Benz, R., Altamura, S., Goede, J. S., Muckenthaler, M. U., & Levi, S.
Affiliations
  • Vita-Salute San Raffaele University (IT)
  • Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
  • Kantonsspital Münsterlingen (CH)
  • Heidelberg University (DE)
  • University Hospital Zurich (CH)
Corresponding author
Levi, Sonia
Venue
Journal of Experimental Medicine
Published
2013-08-12
Volume
210
Issue
9
Pages
1779-1791
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
OpenAlex
W2134438683
Cited by
47
References
78
Citations by year
2026: 1 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 1 · 2015: 7 · 2014: 7
FWCI
3.59
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
Dietmar Hopp Stiftung
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
  • Health Sciences › Medicine › Epidemiology › Restless Legs Syndrome Research
Keywords
ferritin light chain, iron homeostasis, ferroxidase activity, FTH1, catalase, superoxide dismutase 1, reactive oxygen species, protein oxidation, fibroblasts, loss-of-function mutations, iron storage
MeSH terms
Iron Deficiencies, Amino Acid Sequence, Apoferritins, Base Sequence, Child, Female, Fibroblasts, Half-Life, Homozygote, Humans, Iron, Molecular Sequence Data, Neurons, Receptors, Transferrin, Restless Legs Syndrome, Seizures, Reactive Oxygen Species, Oxidative Stress, Codon, Terminator, Membrane Potential, Mitochondrial, Young Adult, Polymerization

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