Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome.
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.
San Raffaele Scientific Institute, Division of Neuroscience and 2 University Vita-Salute San Raffaele, Milan, Italy.
Anna
A
Cozzi
Paolo
P
Santambrogio
Daniela
D
Privitera
Vania
V
Broccoli
Luisa Ida
LI
Rotundo
Barbara
B
Garavaglia
Rudolf
R
Benz
Sandro
S
Altamura
Jeroen S
JS
Goede
Martina U
MU
Muckenthaler
Sonia
S
Levi
D000595:Amino Acid Sequence; D001052:Apoferritins / Q000737:chemistry / Q000172:deficiency* / Q000378:metabolism; D001483:Base Sequence; D002648:Child; D018388:Codon, Terminator / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006207:Half-Life; D006720:Homozygote; D006801:Humans; D007501:Iron / Q000378:metabolism; D000090463:Iron Deficiencies; D053078:Membrane Potential, Mitochondrial; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D058105:Polymerization; D017382:Reactive Oxygen Species / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D012148:Restless Legs Syndrome / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D018388:Codon, Terminator; C507433:FTL protein, human; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; D001052:Apoferritins; D007501:Iron