RBCC Red Blood Cell Collection

FTL [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Ferritin light chain; Ferritin L subunit
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P02792
ID FRIL_HUMAN Reviewed; 175 AA.
AC P02792; B2R4B9; Q6IBT7; Q7Z2W1; Q86WI9; Q8WU07; Q96AU9; Q96CU0;
read moreAC Q9BTZ8;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 152.
DE RecName: Full=Ferritin light chain;
DE Short=Ferritin L subunit;
GN Name=FTL;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3840162;
RA Boyd D., Vecoli C., Belcher D.M., Jain S.K., Drysdale J.W.;
RT "Structural and functional relationships of human ferritin H and L
RT chains deduced from cDNA clones.";
RL J. Biol. Chem. 260:11755-11761(1985).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3858810; DOI=10.1073/pnas.82.10.3139;
RA Dorner M.H., Salfeld J., Will H., Leibold E.A., Vass J.K., Munro H.N.;
RT "Structure of human ferritin light subunit messenger RNA: comparison
RT with heavy subunit message and functional implications.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:3139-3143(1985).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=3754330; DOI=10.1093/nar/14.7.2863;
RA Santoro C., Marone M., Ferrone M., Costanzo F., Colombo M.,
RA Minganti C., Cortese R., Silengo L.;
RT "Cloning of the gene coding for human L apoferritin.";
RL Nucleic Acids Res. 14:2863-2876(1986).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Jordan T.P., Li X.G., Bhatti A.F., Obunike J.C., Tilson M.D.;
RT "Expression of a ferritin-like mRNA by abdominal aortic aneurysm (AAA)
RT adventitial fibroblasts.";
RL Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon endothelium;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Skin, Testis, and Urinary bladder;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 33-175.
RX PubMed=3023856;
RA Chou C.-C., Gatti R.A., Fuller M.L., Concannon P., Wong A., Chada S.,
RA Davis R.C., Salser W.A.;
RT "Structure and expression of ferritin genes in a human promyelocytic
RT cell line that differentiates in vitro.";
RL Mol. Cell. Biol. 6:566-573(1986).
RN [11]
RP PROTEIN SEQUENCE OF 2-36 AND 41-175.
RC TISSUE=Liver;
RX PubMed=6653779; DOI=10.1016/0014-5793(83)80037-4;
RA Addison J.M., Fitton J.E., Lewis W.G., May K., Harrison P.M.;
RT "The amino acid sequence of human liver apoferritin.";
RL FEBS Lett. 164:139-144(1983).
RN [12]
RP PROTEIN SEQUENCE OF 84-90 AND 145-155.
RC TISSUE=Placenta;
RX PubMed=8706699; DOI=10.1111/j.1432-1033.1996.0144u.x;
RA Vladimirov S.N., Ivanov A.V., Karpova G.G., Musolyamov A.K.,
RA Egorov T.A., Thiede B., Wittmann-Liebold B., Otto A.;
RT "Characterization of the human small-ribosomal-subunit proteins by N-
RT terminal and internal sequencing, and mass spectrometry.";
RL Eur. J. Biochem. 239:144-149(1996).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 2-174, AND SUBUNIT.
RX PubMed=16790936; DOI=10.1107/S0907444906018294;
RA Wang Z., Li C., Ellenburg M., Soistman E., Ruble J., Wright B.,
RA Ho J.X., Carter D.C.;
RT "Structure of human ferritin L chain.";
RL Acta Crystallogr. D 62:800-806(2006).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF 1-191, FUNCTION, SUBUNIT,
RP AND DOMAIN.
RX PubMed=19923220; DOI=10.1074/jbc.M109.042986;
RA Baraibar M.A., Muhoberac B.B., Garringer H.J., Hurley T.D., Vidal R.;
RT "Unraveling of the E-helices and disruption of 4-fold pores are
RT associated with iron mishandling in a mutant ferritin causing
RT neurodegeneration.";
RL J. Biol. Chem. 285:1950-1956(2010).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 1-166, FUNCTION, SUBUNIT,
RP DOMAIN, FUNCTION AS A FERROXIDASE, MASS SPECTROMETRY, AND ROLE IN
RP DISEASE.
RX PubMed=20159981; DOI=10.1074/jbc.M109.096404;
RA Luscieti S., Santambrogio P., Langlois d'Estaintot B., Granier T.,
RA Cozzi A., Poli M., Gallois B., Finazzi D., Cattaneo A., Levi S.,
RA Arosio P.;
RT "Mutant ferritin L-chains that cause neurodegeneration act in a
RT dominant-negative manner to reduce ferritin iron incorporation.";
RL J. Biol. Chem. 285:11948-11957(2010).
RN [17]
RP VARIANT NBIA3 THR-96.
RX PubMed=16116125; DOI=10.1212/01.wnl.0000178224.81169.c2;
RA Maciel P., Cruz V.T., Constante M., Iniesta I., Costa M.C.,
RA Gallati S., Sousa N., Sequeiros J., Coutinho P., Santos M.M.;
RT "Neuroferritinopathy: missense mutation in FTL causing early-onset
RT bilateral pallidal involvement.";
RL Neurology 65:603-605(2005).
CC -!- FUNCTION: Stores iron in a soluble, non-toxic, readily available
CC form. Important for iron homeostasis. Iron is taken up in the
CC ferrous form and deposited as ferric hydroxides after oxidation.
CC Also plays a role in delivery of iron to cells. Mediates iron
CC uptake in capsule cells of the developing kidney (By similarity).
CC -!- SUBUNIT: Oligomer of 24 subunits. There are two types of subunits:
CC L (light) chain and H (heavy) chain. The major chain can be light
CC or heavy, depending on the species and tissue type. The functional
CC molecule forms a roughly spherical shell with a diameter of 12 nm
CC and contains a central cavity into which the insoluble mineral
CC iron core is deposited. Iron enters the spherical protein shell
CC through pores that are formed between subunits. Mutations leading
CC to truncation or the addition of extra residues at the C-terminus
CC interfere with normal pore formation and with iron accumulation.
CC -!- INTERACTION:
CC Self; NbExp=5; IntAct=EBI-713279, EBI-713279;
CC P02794:FTH1; NbExp=3; IntAct=EBI-713279, EBI-713259;
CC P42858:HTT; NbExp=2; IntAct=EBI-713279, EBI-466029;
CC P43490:NAMPT; NbExp=3; IntAct=EBI-713279, EBI-2829310;
CC -!- DISEASE: Hereditary hyperferritinemia-cataract syndrome (HHCS)
CC [MIM:600886]: Autosomal dominant disease characterized by early-
CC onset bilateral cataract. Affected patients have elevated level of
CC circulating ferritin. HHCS is caused by mutations in the iron
CC responsive element (IRE) of the FTL gene. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Neurodegeneration with brain iron accumulation 3 (NBIA3)
CC [MIM:606159]: A neurodegenerative disorder associated with iron
CC accumulation in the brain, primarily in the basal ganglia. It is
CC characterized by a variety of neurological signs including
CC parkinsonism, ataxia, corticospinal signs, mild non-progressive
CC cognitive deficit and episodic psychosis. It is linked with
CC decreased serum ferritin levels. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the ferritin family.
CC -!- SIMILARITY: Contains 1 ferritin-like diiron domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAE11873.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FTL";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Ferritin entry;
CC URL="http://en.wikipedia.org/wiki/Ferritin";
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DR EMBL; M11147; AAA52439.1; -; mRNA.
DR EMBL; M10119; AAA35831.1; -; mRNA.
DR EMBL; M12938; AAA52440.1; -; mRNA.
DR EMBL; AY207005; AAO52739.1; -; mRNA.
DR EMBL; CR456715; CAG32996.1; -; mRNA.
DR EMBL; AK311773; BAG34716.1; -; mRNA.
DR EMBL; BX571748; CAE11873.1; ALT_INIT; mRNA.
DR EMBL; AC026803; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC002991; AAH02991.2; -; mRNA.
DR EMBL; BC004245; AAH04245.1; -; mRNA.
DR EMBL; BC008439; AAH08439.1; -; mRNA.
DR EMBL; BC013928; AAH13928.1; -; mRNA.
DR EMBL; BC016715; AAH16715.1; -; mRNA.
DR EMBL; BC016346; AAH16346.1; -; mRNA.
DR EMBL; BC016354; AAH16354.1; -; mRNA.
DR EMBL; BC018990; AAH18990.1; -; mRNA.
DR EMBL; BC021670; AAH21670.1; -; mRNA.
DR EMBL; BC058820; AAH58820.1; -; mRNA.
DR EMBL; BC062708; AAH62708.1; -; mRNA.
DR EMBL; X03742; CAA27382.1; -; Genomic_DNA.
DR EMBL; X03743; CAA27383.1; -; Genomic_DNA.
DR EMBL; X03743; CAA27384.1; -; Genomic_DNA.
DR PIR; B23920; FRHUL.
DR RefSeq; NP_000137.2; NM_000146.3.
DR UniGene; Hs.433670; -.
DR UniGene; Hs.728304; -.
DR PDB; 2FFX; X-ray; 1.90 A; J=2-173.
DR PDB; 2FG4; X-ray; 2.10 A; A=2-174.
DR PDB; 2FG8; X-ray; 2.50 A; A/B/C/D/E/F/G/H=2-174.
DR PDB; 3HX2; X-ray; 2.85 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/a/b/c/d/e/f/g/h/i/j/k/l/m/n/o/p/q/r/s/t/u/v/w/x=1-175.
DR PDB; 3HX5; X-ray; 2.85 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/a/b/c/d/e/f/g/h/i/j/k/l/m/n/o/p/q/r/s/t/u/v/w/x=1-175.
DR PDB; 3HX7; X-ray; 2.85 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/a/b/c/d/e/f/g/h/i/j/k/l/m/n/o/p/q/r/s/t/u/v/w/x=1-175.
DR PDB; 3KXU; X-ray; 1.85 A; A=1-166.
DR PDBsum; 2FFX; -.
DR PDBsum; 2FG4; -.
DR PDBsum; 2FG8; -.
DR PDBsum; 3HX2; -.
DR PDBsum; 3HX5; -.
DR PDBsum; 3HX7; -.
DR PDBsum; 3KXU; -.
DR ProteinModelPortal; P02792; -.
DR SMR; P02792; 2-157.
DR DIP; DIP-31248N; -.
DR IntAct; P02792; 16.
DR MINT; MINT-1187221; -.
DR STRING; 9606.ENSP00000366525; -.
DR DrugBank; DB00893; Iron Dextran.
DR PhosphoSite; P02792; -.
DR DMDM; 120523; -.
DR PaxDb; P02792; -.
DR PRIDE; P02792; -.
DR DNASU; 2512; -.
DR Ensembl; ENST00000331825; ENSP00000366525; ENSG00000087086.
DR GeneID; 2512; -.
DR KEGG; hsa:2512; -.
DR UCSC; uc002plo.3; human.
DR CTD; 2512; -.
DR GeneCards; GC19P049468; -.
DR HGNC; HGNC:3999; FTL.
DR HPA; CAB020769; -.
DR MIM; 134790; gene.
DR MIM; 600886; phenotype.
DR MIM; 606159; phenotype.
DR neXtProt; NX_P02792; -.
DR Orphanet; 254704; Genetic hyperferritinemia without iron overload.
DR Orphanet; 163; Hereditary hyperferritinemia with congenital cataracts.
DR Orphanet; 157846; Neuroferritinopathy.
DR PharmGKB; PA28412; -.
DR eggNOG; NOG321513; -.
DR HOVERGEN; HBG000410; -.
DR InParanoid; P02792; -.
DR KO; K13625; -.
DR OMA; MYLQASY; -.
DR OrthoDB; EOG7DRJ49; -.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR Reactome; REACT_160300; Binding and Uptake of Ligands by Scavenger Receptors.
DR ChiTaRS; FTL; human.
DR EvolutionaryTrace; P02792; -.
DR GeneWiki; Ferritin_light_chain; -.
DR GenomeRNAi; 2512; -.
DR NextBio; 9899; -.
DR PRO; PR:P02792; -.
DR ArrayExpress; P02792; -.
DR Bgee; P02792; -.
DR CleanEx; HS_FTL; -.
DR Genevestigator; P02792; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0008043; C:intracellular ferritin complex; IDA:UniProtKB.
DR GO; GO:0008199; F:ferric iron binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IDA:UniProtKB.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0006879; P:cellular iron ion homeostasis; TAS:Reactome.
DR GO; GO:0006826; P:iron ion transport; IEA:InterPro.
DR GO; GO:0006892; P:post-Golgi vesicle-mediated transport; TAS:Reactome.
DR GO; GO:0055085; P:transmembrane transport; TAS:Reactome.
DR Gene3D; 1.20.1260.10; -; 1.
DR InterPro; IPR001519; Ferritin.
DR InterPro; IPR009040; Ferritin-like_diiron.
DR InterPro; IPR009078; Ferritin-like_SF.
DR InterPro; IPR012347; Ferritin-rel.
DR InterPro; IPR014034; Ferritin_CS.
DR InterPro; IPR008331; Ferritin_DPS_dom.
DR PANTHER; PTHR11431; PTHR11431; 1.
DR Pfam; PF00210; Ferritin; 1.
DR SUPFAM; SSF47240; SSF47240; 1.
DR PROSITE; PS00540; FERRITIN_1; 1.
DR PROSITE; PS00204; FERRITIN_2; 1.
DR PROSITE; PS50905; FERRITIN_LIKE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome;
KW Direct protein sequencing; Disease mutation; Iron; Iron storage;
KW Metal-binding; Neurodegeneration; Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 175 Ferritin light chain.
FT /FTId=PRO_0000201060.
FT DOMAIN 7 156 Ferritin-like diiron.
FT REGION 54 61 Catalytic site for iron oxidation.
FT METAL 54 54 Iron.
FT METAL 57 57 Iron.
FT METAL 58 58 Iron.
FT METAL 61 61 Iron.
FT METAL 64 64 Iron.
FT MOD_RES 2 2 N-acetylserine.
FT VARIANT 96 96 A -> T (in NBIA3).
FT /FTId=VAR_026633.
FT CONFLICT 54 54 E -> Q (in Ref. 11; AA sequence).
FT CONFLICT 87 87 E -> Q (in Ref. 11; AA sequence).
FT CONFLICT 89 89 E -> W (in Ref. 12; AA sequence).
FT CONFLICT 102 102 A -> T (in Ref. 2; AAA35831).
FT CONFLICT 154 154 R -> A (in Ref. 12; AA sequence).
FT CONFLICT 175 175 D -> N (in Ref. 11; AA sequence).
FT TURN 3 5
FT HELIX 11 39
FT TURN 41 43
FT HELIX 46 73
FT HELIX 93 120
FT HELIX 124 133
FT HELIX 135 154
FT STRAND 155 157
FT HELIX 160 170
SQ SEQUENCE 175 AA; 20020 MW; 0DB98081FF976BC2 CRC64;
MSSQIRQNYS TDVEAAVNSL VNLYLQASYT YLSLGFYFDR DDVALEGVSH FFRELAEEKR
EGYERLLKMQ NQRGGRALFQ DIKKPAEDEW GKTPDAMKAA MALEKKLNQA LLDLHALGSA
RTDPHLCDFL ETHFLDEEVK LIKKMGDHLT NLHRLGGPEA GLGEYLFERL TLKHD
//

MIM 134790
*RECORD*
*FIELD* NO
134790
*FIELD* TI
*134790 FERRITIN LIGHT CHAIN; FTL
*FIELD* TX

DESCRIPTION

The iron storage protein ferritin is a complex of 24 L-ferritin (FTL)
read moreand 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).

CLONING

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.

MAPPING

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.

GENE FUNCTION

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.

MOLECULAR GENETICS

- Hyperferritinemia-Cataract Syndrome

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 (HHCS; 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, 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.

GENOTYPE/PHENOTYPE CORRELATIONS

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).

ANIMAL MODEL

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.

*FIELD* AV
.0001
HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
FTL, -160A-G

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 (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.

.0002
HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
FTL, -159G-C

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
(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.

.0003
HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
FTL, -168G-A

Luscieti et al. (2013) referred to this mutation as c.-168G-A (+32G-A)
(Luscieti et al., 2013).

Cazzola et al. (1997) studied 2 families with hyperferritinemia and
congenital cataract (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 point mutation in the IRE of
the L-subunit: a single G-to-A transition of 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.

.0004
HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
FTL, -182C-T AND -178T-G

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 (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.

.0005
HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
FTL, 29-BP DEL, NT-190

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 (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.

.0006
HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
FTL, -168G-T

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 (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.

.0007
HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
FTL, -161C-T

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 (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 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.

.0008
HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
FTL, -164C-A

Luscieti et al. (2013) referred to this mutation as c.-164C-A (+36C-A).

See 134790.0007 and Mumford et al. (1998).

.0009
HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
FTL, -149G-C

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 (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.

.0010
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 3
FTL, 1-BP INS, 460A

In a large family segregating an autosomal dominant basal ganglia
disease, known as neurodegeneration with brain iron accumulation-3 or
neuroferritinopathy (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.

.0011
HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
FTL, 6-BP DEL, NT-178

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 (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.

.0012
HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
FTL, -168G-C

Luscieti et al. (2013) referred to this mutation as c.-168G-C (+32G-C).

In affected members of a family with hyperferritinemia-cataract syndrome
(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.

.0013
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 3
FTL, ALA96THR

In a 19-year-old man with parkinsonism, ataxia, and corticospinal signs
consistent with neuroferritinopathy (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.

.0014
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 3
FTL, 2-BP INS, 498TC

In affected members of a large French family with neuroferritinopathy
(606159), Vidal et al. (2004) identified a heterozygous 2-bp insertion
(498insTC) 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.

.0015
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 3
FTL, 16-BP DUP, NT469

In a Japanese mother and son with neuroferritinopathy (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.

.0016
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 3
FTL, 1-BP DUP, 458A

In affected members of a French family with neuroferritinopathy
(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).

.0017
HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
FTL, THR30ILE

In 17 unrelated patients with hyperferritinemia (600886), 1 of whom had
bilateral cataract, Kannengiesser et al. (2009) identified
heterozygosity for a 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.

.0018
L-FERRITIN DEFICIENCY, AUTOSOMAL DOMINANT
FTL, MET1VAL

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.

.0019
L-FERRITIN DEFICIENCY, AUTOSOMAL RECESSIVE
FTL, GLU104TER

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.

.0020
HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
FTL, -164C-T

In affected members of a Spanish family with hyperferritinemia with or
without cataract (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.

*FIELD* SA
Dorner et al. (1985)
*FIELD* RF
1. Aguilar-Martinez, P.; Biron, C.; Masmejean, C.; Jeanjean, P.; Schved,
J.-F.: A novel mutation in the iron responsive element of ferritin
L-subunit gene as a cause for hereditary hyperferritinemia-cataract
syndrome. (Letter) Blood 88: 1895-1903, 1996.

2. Beaumont, C.; Leneuve, P.; Devaux, I.; Scoazec, J.-Y.; Berthier,
M.; Loiseau, M.-N.; Grandchamp, B.; Bonneau, D.: Mutation in the
iron responsive element of the L ferritin mRNA in a family with dominant
hyperferritinaemia and cataract. Nature Genet. 11: 444-446, 1995.

3. Brown, A. J. P.; Leibold, E. A.; Munro, H. N.: Isolation of cDNA
clones for the light subunit of rat liver ferritin: evidence that
the light subunit is encoded by a multigene family. Proc. Nat. Acad.
Sci. 80: 1265-1269, 1983.

4. Camaschella, C.; Zecchina, G.; Lockitch, G.; Roetto, A.; Campanella,
A.; Arosio, P.; Levi, S.: A new mutation (G51C) in the iron-responsive
element (IRE) of L-ferritin associated with hyperferritinaemia-cataract
syndrome decreases the binding affinity of the mutated IRE for iron-regulatory
proteins. Brit. J. Haemat. 108: 480-482, 2000.

5. Campagnoli, M. F.; Pimazzoni, R.; Bosio, S.; Zecchina, G.; DeGobbi,
M.; Bosso, P.; Oldani, B.; Ramenghi, U.: Onset of cataract in early
infancy associated with a 32G-C transition in the iron responsive
element of L-ferritin. Europ. J. Pediat. 161: 499-502, 2002.

6. Caskey, J. H.; Jones, C.; Miller, Y. E.; Seligman, P. A.: Human
ferritin gene is assigned to chromosome 19. Proc. Nat. Acad. Sci. 80:
482-486, 1983.

7. Cazzola, M.; Bergamaschi, G.; Tonon, L.; Arbustini, E.; Grasso,
M.; Vercesi, E.; Barosi, G.; Bianchi, P. E.; Cairo, G.; Arosio, P.
: Hereditary hyperferritinemia-cataract syndrome: relationship between
phenotypes and specific mutations in the iron-responsive element of
ferritin light-chain mRNA. Blood 90: 814-821, 1997.

8. Cazzola, M.; Foglieni, B.; Bergamaschi, G.; Levi, S.; Lazzarino,
M.; Arosio, P.: A novel deletion of the L-ferritin iron-responsive
element responsible for severe hereditary hyperferritinaemia-cataract
syndrome. Brit. J. Haemat. 116: 667-670, 2002.

9. Chinnery, P. F.; Curtis, A. R. J.; Fey, C.; Coulthard, A.; Crompton,
D.; Curtis, A.; Lombes, A.; Burn, J.: Neuroferritinopathy in a French
family with late onset dominant dystonia. J. Med. Genet. 40: e69,
2003. Note: Electronic Article.

10. 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.: Human L-ferritin deficiency is characterized by
idiopathic generalized seizures and atypical restless leg syndrome. J.
Exp. Med. 210: 1779-1791, 2013.

11. Cremonesi, L.; Cozzi, A.; Girelli, D.; Ferrari, F.; Fermo, I.;
Foglieni, B.; Levi, S.; Bozzini, C.; Camparini, M.; Ferrari, M.; Arosio,
P.: Case report: a subject with a mutation in the ATG start codon
of L-ferritin has no haematological or neurological symptoms. J.
Med. Genet. 41: e81, 2004. Note: Electronic Article.

12. Curtis, A. R. J.; Fey, C.; Morris, C. M.; Bindoff, L. A.; Ince,
P. G.; Chinnery, P. F.; Coulthard, A.; Jackson, M. J.; Jackson, A.
P.; McHale, D. P.; Hay, D.; Barker, W. A.; Markham, A. F.; Bates,
D.; Curtis, A.; Burn, J.: Mutation in the gene encoding ferritin
light polypeptide causes dominant adult-onset basal ganglia disease. Nature
Genet. 28: 350-354, 2001.

13. Devos, D.; Tchofo, P. J.; Vuillaume, I.; Destee, A.; Batey, S.;
Burn, J.; Chinnery, P. F.: Clinical features and natural history
of neuroferritinopathy caused by the 458dupA FTL mutation. (Letter) Brain 132:
e109, 2009. Note: Electronic Article.

14. Dorner, M. H.; Salfeld, J.; Will, H.; Leibold, E. A.; Vass, J.
K.; Munro, H. N.: Structure of human ferritin light subunit messenger
RNA: comparison with heavy subunit message and functional implications. Proc.
Nat. Acad. Sci. 82: 3139-3143, 1985.

15. Filie, J. D.; Buckler, C. E.; Kozak, C. A.: Genetic mapping of
the mouse ferritin light chain gene and 11 pseudogenes on 11 mouse
chromosomes. Mammalian Genome 9: 111-113, 1998.

16. Giansily-Blaizot, M.; Cunat, S.; Moulis, G.; Schved, J.-F.; Aguilar-Martinez,
P.: Homozygous mutation of the 5-prime UTR region of the L-ferritin
gene in the hereditary hyperferritinemia cataract syndrome and its
impact on the phenotype. (Letter) Haematologica 98: e42, 2013. Note:
Electronic Article.

17. Girelli, D.; Bozzini, C.; Zecchina, G.; Tinazzi, E.; Bosio, S.;
Piperno, A.; Ramenghi, U.; Peters, J.; Levi, S.; Camaschella, C.;
Corrocher, R.: Clinical, biochemical and molecular findings in a
series of families with hereditary hyperferritinaemia-cataract syndrome. Brit.
J. Haemat. 115: 334-340, 2001.

18. Girelli, D.; Corrocher, R.; Bisceglia, L.; Olivieri, O.; De Franceschi,
L.; Zelante, L.; Gasparini, P.: Molecular basis for the recently
described hereditary hyperferritinemia-cataract syndrome: A mutation
in the iron-responsive element of ferritin L-subunit gene (the 'Verona
mutation'). Blood 86: 4050-453, 1995.

19. Girelli, D.; Corrocher, R.; Bisceglia, L.; Olivieri, O.; Zelante,
L.; Panozzo, G.; Gasparini, P.: Hereditary hyperferritinemia-cataract
syndrome caused by a 29-base pair deletion in the iron responsive
element of ferritin L-subunit gene. Blood 90: 2084-2088, 1997.

20. Girelli, D.; Olivieri, O.; De Franceschi, L.; Corrocher, R.; Bergamaschi,
G.; Cazzola, M.: A linkage between hereditary hyperferritinaemia
not related to iron overload and autosomal dominant congenital cataract. Brit.
J. Haemat. 90: 931-934, 1995.

21. Hentze, M. W.; Keim, S.; Papadopoulos, P.; O'Brien, S.; Modi,
W.; Drysdale, J.; Leonard, W. J.; Harford, J. B.; Klausner, R. D.
: Cloning, characterization, expression, and chromosomal localization
of a human ferritin heavy-chain gene. Proc. Nat. Acad. Sci. 83:
7226-7230, 1986.

22. Kannengiesser, C.; Jouanolle, A.-M.; Hetet, G.; Mosser, A.; Muzeau,
F.; Henry, D.; Bardou-Jacquet, E.; Mornet, M.; Brissot, P.; Deugnier,
Y.; Grandchamp, B.; Beaumont, C.: A new missense mutation in the
L ferritin coding sequence associated with elevated levels of glycosylated
ferritin in serum and absence of serum overload. Haematologica 94:
335-339, 2009.

23. Lebo, R. V.; Kan, Y. W.; Cheung, M.-C.; Jain, S. K.; Drysdale,
J.: Human ferritin light chain gene sequences mapped to several sorted
chromosomes. Hum. Genet. 71: 325-328, 1985.

24. Luscieti, S.; Tolle, G.; Aranda, J.; Campos, C. B.; Risse, F.;
Moran, E.; Muckenthaler, M. U.; Sanchez, M.: Novel mutations in the
ferritin-L iron-responsive element that only mildly impair IRP binding
cause hereditary hyperferritinaemia cataract syndrome. Orphanet J.
Rare Dis. 8: 30, 2013. Note: Electronic Article.

25. Maciel, P.; Cruz, V. T.; Constante, M.; Iniesta, I.; Costa, M.
C.; Gallati, S.; Sousa, N.; Sequeiros, J.; Coutinho, P.; Santos, M.
M.: Neuroferritinopathy: missense mutation in FTL causing early-onset
bilateral pallidal involvement. Neurology 65: 603-605, 2005.

26. Martin, M. E.; Fargion, S.; Brissot, P.; Pellat, B.; Beaumont,
C.: A point mutation in the bulge of the iron-responsive element
of the L ferritin gene in two families with the hereditary hyperferritinemia-cataract
syndrome. Blood 91: 319-323, 1998.

27. McGill, J. R.; Boyd, D.; Barrett, K. J.; Drysdale, J. W.; Moore,
C. M.: Localization of human ferritin H (heavy) and L (light) subunits
by in situ hybridization. (Abstract) Am. J. Hum. Genet. 36: 146S,
1984.

28. McLeod, J. L.; Craig, J.; Gumley, S.; Roberts, S.; Kirkland, M.
A.: Mutation spectrum in Australian pedigrees with hereditary hyperferritinaemia-cataract
syndrome reveals novel and de novo mutations. Brit. J. Haemat. 118:
1179-1182, 2002.

29. Mumford, A. D.; Vulliamy, T.; Lindsay, J.; Watson, A.: Hereditary
hyperferritinemia-cataract syndrome: two novel mutations in the L-ferritin
iron-responsive element. (Letter) Blood 91: 367-368, 1998.

30. Munro, H. N.; Aziz, N.; Leibold, E. A.; Murray, M.; Rogers, J.;
Vass, J. K.; White, K.: The ferritin genes: structure, expression,
and regulation. Ann. N.Y. Acad. Sci. 526: 113-123, 1988.

31. Ohta, E.; Nagasaka, T.; Shindo, K.; Toma, S.; Nagasaka, K.; Ohta,
K.; Shiozawa, Z.: Neuroferritinopathy in a Japanese family with a
duplication in the ferritin light chain gene. Neurology 70: 1493-1494,
2008.

32. Sammarco, M. C.; Ditch, S.; Banerjee, A.; Grabczyk, E.: Ferritin
L and H subunits are differentially regulated on a post-transcriptional
level. J. Biol. Chem. 283: 4578-4587, 2008.

33. Santoro, C.; Marone, M.; Ferrone, M.; Costanzo, F.; Colombo, M.;
Minganti, C.; Cortese, R.; Silengo, L.: Cloning of the gene coding
for human L apoferritin. Nucleic Acids Res. 14: 2863-2876, 1986.

34. Shekunov, J.; de Groen, P. C.; Lindor, N. M.; Klee, G. G.; Aleff,
R. A.; Wieben, E. D.; Mohney, B. G.: Hereditary hyperferritinemia-cataract
syndrome in two large multigenerational American families. J. AAPOS 15:
356-361, 2011.

35. Shi, H.; Bencze, K. Z.; Stemmler, T. L.; Philpott, C. C.: A cytosolic
iron chaperone that delivers iron to ferritin. Science 320: 1207-1210,
2008.

36. Vidal, R.; Ghetti, B.; Takao, M.; Brefel-Courbon, C.; Uro-Coste,
E.; Glazier, B. S.; Siani, V.; Benson, M. D.; Calvas, P.; Miravalle,
L.; Rascol, O.; Delisle, M. B.: Intracellular ferritin accumulation
in neural and extraneural tissue characterizes a neurodegenerative
disease associated with a mutation in the ferritin light polypeptide
gene. J. Neuropath. Exp. Neurol. 63: 363-380, 2004.

37. Vidal, R.; Miravalle, L.; Gao, X.; Barbeito, A. G.; Baraibar,
M. A.; Hekmatyar, S. K.; Widel, M.; Bansal, N.; Delisle, M. B.; Ghetti,
B.: Expression of a mutant form of the ferritin light chain gene
induces neurodegeneration and iron overload in transgenic mice. J.
Neurosci. 28: 60-67, 2008.

38. Watanabe, N.; Drysdale, J. W.: Evidence for distinct mRNAs for
ferritin subunits. Biochem. Biophys. Res. Commun. 98: 507-511, 1981.

39. Worwood, M.; Brook, J. D.; Cragg, S. J.; Hellkuhl, B.; Jones,
B. M.; Perera, P.; Roberts, S. H.; Shaw, D. J.: Assignment of human
ferritin genes to chromosomes 11 and 19q13.3-19qter. Hum. Genet. 69:
371-374, 1985.

*FIELD* CN
Cassandra L. Kniffin - updated: 1/15/2014
Patricia A. Hartz - updated: 11/6/2013
Marla J. F. O'Neill - updated: 2/1/2013
Jane Kelly - updated: 2/18/2012
Cassandra L. Kniffin - updated: 2/19/2010
Ada Hamosh - updated: 6/10/2008
Cassandra L. Kniffin - updated: 10/31/2005
Cassandra L. Kniffin - updated: 7/13/2004
Victor A. McKusick - updated: 10/21/2002
Victor A. McKusick - updated: 5/13/2002
Victor A. McKusick - updated: 1/24/2002
Ada Hamosh - updated: 7/30/2001
Victor A. McKusick - updated: 7/13/2000
Victor A. McKusick - updated: 4/10/1998
Victor A. McKusick - updated: 3/25/1998
Victor A. McKusick - updated: 1/21/1998
Victor A. McKusick - updated: 10/29/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 01/15/2014
carol: 1/15/2014
ckniffin: 1/15/2014
mgross: 12/6/2013
mcolton: 11/6/2013
alopez: 2/1/2013
alopez: 2/18/2012
wwang: 6/10/2011
carol: 3/1/2010
ckniffin: 2/19/2010
alopez: 6/12/2008
terry: 6/10/2008
terry: 12/17/2007
wwang: 11/3/2005
ckniffin: 10/31/2005
carol: 7/13/2004
ckniffin: 7/13/2004
tkritzer: 3/19/2003
carol: 3/13/2003
carol: 10/24/2002
tkritzer: 10/21/2002
alopez: 5/21/2002
terry: 5/13/2002
carol: 2/6/2002
mcapotos: 2/4/2002
terry: 1/24/2002
carol: 12/10/2001
alopez: 7/30/2001
terry: 7/30/2001
carol: 7/14/2000
terry: 7/13/2000
carol: 4/10/1998
alopez: 3/30/1998
terry: 3/25/1998
mark: 1/25/1998
terry: 1/21/1998
mark: 11/3/1997
terry: 10/29/1997
alopez: 7/29/1997
mark: 6/14/1997
terry: 4/11/1997
terry: 2/6/1997
mark: 12/16/1996
terry: 11/13/1996
terry: 2/6/1996
mark: 1/22/1996
joanna: 1/17/1996
mark: 12/7/1995
terry: 12/7/1995
mark: 11/7/1995
mimadm: 9/24/1994
carol: 3/26/1992
supermim: 3/16/1992
carol: 12/19/1990
supermim: 3/20/1990

MIM 600886
*RECORD*
*FIELD* NO
600886
*FIELD* TI
#600886 HYPERFERRITINEMIA WITH OR WITHOUT CATARACT
;;HYPERFERRITINEMIA-CATARACT SYNDROME;;
read moreHYPERFERRITINEMIA, HEREDITARY, WITH CONGENITAL CATARACTS; HHCS
*FIELD* TX
A number sign (#) is used with this entry because
hyperferritinemia-cataract syndrome is caused by heterozygous mutation
in the iron-responsive element (IRE) in the 5-prime noncoding region of
the ferritin light chain gene (FTL; 134790) on chromosome 19q13.

Some patients, born in consanguineous families, may carry homozygous
mutations, but they do not appear to have a more severe phenotype
(Giansily-Blaizot et al., 2013; Luscieti et al., 2013).

CLINICAL FEATURES

Girelli et al. (1995) studied 2 Italian families in which a combination
of congenital nuclear cataract and elevated serum ferritin not related
to iron overload was transmitted as an autosomal dominant trait.
Affected individuals had normal serum iron and transferrin saturation,
but high serum ferritin. Red cell counts were normal and venesection
rapidly resulted in iron deficiency anemia. Both families had lived in
northern Italy for many generations, and both had instances of
male-to-male transmission of the trait. Studies with monoclonal
antibodies demonstrated no ferritin H subunit in either normal subjects
or those with hyperferritinemia, but elevation of the ferritin L subunit
in those with elevated serum ferritin. No relationship between high
serum ferritin and HLA type was found. Girelli et al. (1995) noted that
the FTL and MP19 (154045) genes map to 19q.

Bonneau et al. (1995) reported cosegregation of dominantly inherited
cataract with an abnormally high level of serum ferritin in a
3-generation pedigree and suggested 2 possibilities: that the
cataract-hyperferritinemia syndrome is a disorder of ferritin metabolism
leading to lens opacity, or that it is a contiguous gene syndrome
involving the L-ferritin gene and the gene encoding lens membrane
protein MP19 on 19q.

Giansily-Blaizot et al. (2013) reported a 54-year-old woman of Canadian
descent who presented with unexplained hyperferritinemia and microcytic
anemia. Medical history revealed that she was diagnosed with bilateral
cataracts at age 35 years. 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. Genetic analysis identified a homozygous mutation in the
FTL gene (134790.0009). 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.

Luscieti et al. (2013) reported a Spanish family with HHCS. 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. Genetic
analysis identified a homozygous mutation (+36C-U; 134790.0020) in the
proband and her sister, 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. In
vitro studies showed that the mutation caused a mild reduction in the
binding of iron regulatory proteins. The report indicated that
genotype/phenotype correlations in this disorder are difficult to
establish due to inter- and intraindividual variability.

INHERITANCE

The transmission pattern in the families with HHCS reported by Girelli
et al. (1995) and Bonneau et al. (1995) was consistent with autosomal
dominant inheritance. Some patients, born in consanguineous families,
may carry homozygous mutations, but this does not appear to result in a
more severe phenotype (Giansily-Blaizot et al., 2013; Luscieti et al.,
2013).

MOLECULAR GENETICS

In affected members of the family reported by Bonneau et al. (1995),
Beaumont et al. (1995) identified a point mutation in the IRE in the
5-prime noncoding region of the ferritin light chain gene (134790.0001).
The synthesis of ferritin, the iron-storing molecule, is regulated at
the translational level by iron through interaction between a
cytoplasmic protein denoted iron regulatory protein (IRP) or IRE-binding
protein (100880; 147582), and a conserved nucleotide motif present in
the 5-prime noncoding region of all ferritin mRNAs, the IRE. The IRE
region forms a stem-loop structure; when the supply of iron to the cells
is limited, IRP binds to IRE and represses ferritin synthesis. Beaumont
et al. (1995) noted that this was the first mutation affecting the
IRP-IRE interaction and the iron-mediated regulation of ferritin
synthesis. They suggested that excess production of ferritin in tissues
is responsible for the hyperferritinemia and that intracellular
accumulation of ferritin leads to cataract.

In 3 Australian pedigrees with hereditary hyperferritinemia-cataract
syndrome, McLeod et al. (2002) identified mutations in the FTL gene. One
of the mutations was the same as that identified by Beaumont et al.
(1995); see 134790.0001.

Camaschella et al. (2000) reported a father and daughter with 'modest'
hyperferritinemia and a mutation in the IRE of FTL (51G-C; 134790.0009)
who had no history of visual impairment. Upon slit lamp examination,
bilateral fine lenticular changes were observed in both subjects.
Computational analysis predicted that the 51G-C substitution would alter
the conformation of the stem loop without modifying the residues
involved in direct contact with IRPs, and functional analysis showed
that the mutation reduced, but did not abolish, binding to IRPs.
Camaschella et al. (2000) stated that these findings supported a direct
relationship between the structural effect of IRE mutations and
phenotypic expression of HHCS, and indicated an association between the
level of l-ferritin expression and severity of cataract.

Girelli et al. (2001) studied a total of 62 patients in 14 unrelated
families with 9 different mutations in the FTL gene. No relevant
symptoms other than visual impairment were found to be associated with
the syndrome. Marked phenotypic variability was observed, particularly
with regard to ocular involvement; in 16 subjects with the 39C-T
mutation in the FTL gene (134790.0007), age at diagnosis for cataract
ranged from 6 to 40 years. Similarly, serum ferritin levels varied
substantially between subjects sharing the same mutation. One infant
lacked cataracts at birth and at age 1 year, suggesting that the
cataract is not necessarily congenital. Ferritin content of the lens
removed at surgery in 2 family members was about 1,500-fold higher than
in controls. The cataract as viewed by slit-lamp was described as a
'pulverulent' cataract in some patients and as a 'sunflower' cataract in
others. Girelli et al. (2001) presented a pedigree of an affected
4-generation family with a 29-bp deletion (134790.0005) in the FTL gene
that removed most of the IRE.

In affected members of a family with hyperferritinemia-cataract
syndrome, Campagnoli et al. (2002) identified a heterozygous mutation in
the FTL gene (134790.0012). Two sisters in the last generation developed
cataracts at age 18 months, earlier than most reported cases. The
authors suggested that the early onset rules out the possibility that
cataracts in this syndrome are due to age-accumulation of ferritin.

In a healthy 52-year-old woman who was a control subject in a genetic
study of hyperferritinemia-cataract syndrome, Cremonesi et al. (2004)
identified a heterozygous mutation in the ATG start codon of the FTL
gene, predicted to disable protein translation and expression. She had
no history of iron deficiency anemia or neurologic dysfunction.
Hematologic examination was normal except for decreased serum ferritin.
The findings suggested that L-ferritin has no effect on systemic iron
metabolism and also indicated that neuroferritinopathy is not a
consequence of haploinsufficiency of L-ferritin, but likely results from
gain-of-function mutations in the FTL gene.

Kannengiesser et al. (2009) analyzed the FTL gene in 91 probands with
hyperferritinemia, including 25 familial cases and 66 isolated cases.
Some patients were referred for early-onset cataract, but none had an
IRE mutation in FTL exon 1; however, heterozygosity for a missense
mutation in the N terminus (T30I; 134790.0017) was identified in 12
familial and 5 isolated probands, 1 of whom had bilateral cataract. The
mutation segregated with disease in the 10 families that underwent
cosegregation analysis. 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 mutation-positive individuals, 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.

GENOTYPE/PHENOTYPE CORRELATIONS

In 7 kindreds from the United Kingdom with hyperferritinemia-cataract
syndrome containing 49 individuals with premature cataract, Lachlan et
al. (2004) found that the severity of the clinical phenotype was
variable both within and between kindreds and showed no clear
relationship with FTL genotype, confirming the findings reported by
Girelli et al. (2001) in a European case series.

*FIELD* RF
1. Beaumont, C.; Leneuve, P.; Devaux, I.; Scoazec, J.-Y.; Berthier,
M.; Loiseau, M.-N.; Grandchamp, B.; Bonneau, D.: Mutation in the
iron responsive element of the L ferritin mRNA in a family with dominant
hyperferritinaemia and cataract. Nature Genet. 11: 444-446, 1995.

2. Bonneau, D.; Winter-Fuseau, I.; Loiseau, M.-N.; Amati, P.; Berthier,
M.; Oriot, D.; Beaumont, C.: Bilateral cataract and high serum ferritin:
a new dominant genetic disorder? J. Med. Genet. 32: 778-779, 1995.

3. Camaschella, C.; Zecchina, G.; Lockitch, G.; Roetto, A.; Campanella,
A.; Arosio, P.; Levi, S.: A new mutation (G51C) in the iron-responsive
element (IRE) of L-ferritin associated with hyperferritinaemia-cataract
syndrome decreases the binding affinity of the mutated IRE for iron-regulatory
proteins. Brit. J. Haemat. 108: 480-482, 2000.

4. Campagnoli, M. F.; Pimazzoni, R.; Bosio, S.; Zecchina, G.; DeGobbi,
M.; Bosso, P.; Oldani, B.; Ramenghi, U.: Onset of cataract in early
infancy associated with a 32G-C transition in the iron responsive
element of L-ferritin. Europ. J. Pediat. 161: 499-502, 2002.

5. Cremonesi, L.; Cozzi, A.; Girelli, D.; Ferrari, F.; Fermo, I.;
Foglieni, B.; Levi, S.; Bozzini, C.; Camparini, M.; Ferrari, M.; Arosio,
P.: Case report: a subject with a mutation in the ATG start codon
of L-ferritin has no haematological or neurological symptoms. J.
Med. Genet. 41: e81, 2004. Note: Electronic Article.

6. Giansily-Blaizot, M.; Cunat, S.; Moulis, G.; Schved, J.-F.; Aguilar-Martinez,
P.: Homozygous mutation of the 5-prime UTR region of the L-Ferritin
gene in the hereditary hyperferritinemia cataract syndrome and its
impact on the phenotype. (Letter) Haematologia 98: e42, 2013. Note:
Electronic Article.

7. Girelli, D.; Bozzini, C.; Zecchina, G.; Tinazzi, E.; Bosio, S.;
Piperno, A.; Ramenghi, U.; Peters, J.; Levi, S.; Camaschella, C.;
Corrocher, R.: Clinical, biochemical and molecular findings in a
series of families with hereditary hyperferritinaemia-cataract syndrome. Brit.
J. Haemat. 115: 334-340, 2001.

8. Girelli, D.; Olivieri, O.; De Franceschi, L.; Corrocher, R.; Bergamaschi,
G.; Cazzola, M.: A linkage between hereditary hyperferritinaemia
not related to iron overload and autosomal dominant congenital cataract. Brit.
J. Haemat. 90: 931-934, 1995.

9. Kannengiesser, C.; Jouanolle, A.-M.; Hetet, G.; Mosser, A.; Muzeau,
F.; Henry, D.; Bardou-Jacquet, E.; Mornet, M.; Brissot, P.; Deugnier,
Y.; Grandchamp, B.; Beaumont, C.: A new missense mutation in the
L ferritin coding sequence associated with elevated levels of glycosylated
ferritin in serum and absence of serum overload. Haematologica 94:
335-339, 2009.

10. Lachlan, K. L.; Temple, I. K.; Mumford, A. D.: Clinical features
and molecular analysis of seven British kindreds with hereditary hyperferritinaemia
cataract syndrome. Europ. J. Hum. Genet. 12: 790-796, 2004.

11. Luscieti, S.; Tolle, G.; Aranda, J.; Campos, C. B.; Risse, F.;
Moran, E.; Muckenthaler, M. U.; Sanchez, M.: Novel mutations in the
ferritin-L iron-responsive element that only mildly impair IRP binding
cause hereditary hyperferritinaemia cataract syndrome. Orphanet J.
Rare Dis. 8: 30, 2013. Note: Electronic Article.

12. McLeod, J. L.; Craig, J.; Gumley, S.; Roberts, S.; Kirkland, M.
A.: Mutation spectrum in Australian pedigrees with hereditary hyperferritinaemia-cataract
syndrome reveals novel and de novo mutations. Brit. J. Haemat. 118:
1179-1182, 2002.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Congenital nuclear cataract (in some patients);
Pulverulent cataract (in some patients);
'Sunflower' cataract (in some patients)

LABORATORY ABNORMALITIES:
Elevated serum ferritin;
Normal serum iron;
Normal transferrin saturation;
Normal red cell counts;
Elevated ferritin L subunit;
Serum ferritin hyperglycosylation

MISCELLANEOUS:
Cataracts may be subclinical in some patients;
Age at diagnosis of cataract may range up to 40 years;
Severity of clinical phenotype varies both within and between kindreds

MOLECULAR BASIS:
Caused by mutation in the ferritin light chain gene (FTL, 134790.0001)

*FIELD* CN
Marla J. F. O'Neill - revised: 04/25/2013

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 04/25/2013

*FIELD* CN
Cassandra L. Kniffin - updated: 1/15/2014
Marla J. F. O'Neill - updated: 2/1/2013
Cassandra L. Kniffin - updated: 5/14/2007
Marla J. F. O'Neill - updated: 11/5/2004
Cassandra L. Kniffin - updated: 7/13/2004
Victor A. McKusick - updated: 10/21/2002
Victor A. McKusick - updated: 1/24/2002

*FIELD* CD
Victor A. McKusick: 11/6/1995

*FIELD* ED
carol: 01/15/2014
ckniffin: 1/15/2014
carol: 12/19/2013
alopez: 2/1/2013
terry: 4/30/2010
wwang: 5/16/2007
ckniffin: 5/14/2007
tkritzer: 11/5/2004
carol: 7/13/2004
ckniffin: 7/13/2004
carol: 10/24/2002
tkritzer: 10/21/2002
carol: 2/6/2002
mcapotos: 2/4/2002
terry: 1/24/2002
carol: 7/12/2000
carol: 5/18/1999
carol: 1/6/1999
jamie: 12/18/1996
mark: 12/7/1995
terry: 12/7/1995
mark: 11/6/1995

MIM 606159
*RECORD*
*FIELD* NO
606159
*FIELD* TI
#606159 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 3; NBIA3
;;NEUROFERRITINOPATHY;;
read moreBASAL GANGLIA DISEASE, ADULT-ONSET
*FIELD* TX
A number sign (#) is used with this entry because this form of
neurodegeneration with brain iron accumulation (NBIA), here designated
'NBIA3,' is caused by mutation in the FTL gene (134790). See
NOMENCLATURE section.

Hyperferritinemia-cataract syndrome (600886) is an allelic disorder with
a different phenotype.

For a general phenotypic description and a discussion of genetic
heterogeneity of NBIA, see NBIA1 (234200).

DESCRIPTION

Neurodegeneration with brain iron accumulation is a genetically
heterogeneous disorder characterized by progressive iron accumulation in
the basal ganglia and other regions of the brain, resulting in
extrapyramidal movements, such as parkinsonism and dystonia. Age at
onset, cognitive involvement, and mode of inheritance is variable
(review by Gregory et al., 2009).

CLINICAL FEATURES

Curtis et al. (2001) described a dominantly inherited late-onset basal
ganglia disease variably presenting with extrapyramidal features similar
to those of Huntington disease (143100) or parkinsonism. The disorder
typically presented with involuntary movements at 40 to 55 years of age.
Symptoms of extrapyramidal dysfunction included choreoathetosis,
dystonia, spasticity, and rigidity, sometimes showing acute progression
but not associated with significant cognitive decline or cerebellar
involvement. MRI scan showed cavitation of the basal ganglia confirmed
by brain pathology. Surviving affected family members lived within a
40-km radius of the home of the earliest founder that was traced (from
records circa 1790), a member of a local family from the Cumbrian region
of northern England. Patients had low serum ferritin levels and abnormal
aggregates of ferritin and iron in the brain. Curtis et al. (2001) noted
that iron deposition in the brain increases normally with age,
especially in the basal ganglia, and is a suspected causative factor in
several neurodegenerative diseases in which it correlates with visible
pathology, possibly by its involvement in toxic free-radical reactions.
Known neurologic disorders were excluded by routine diagnostic tests.

Chinnery et al. (2003) reported a French family in which 7 members
developed dystonia between the ages of 24 and 58 years of age.
Inheritance was autosomal dominant. Additional clinical features
included dysarthria, chorea, parkinsonism, blepharospasm, and cerebellar
signs. Two affected members had a frontal lobe syndrome, and 1 had
dementia. MRI of 3 affected family members showed cystic changes in the
basal ganglia. Skeletal muscle biopsy from 4 patients showed
abnormalities of the mitochondrial respiratory chain. Devos et al.
(2009) provided further information on 4 of the affected members from
the French family reported by Chinnery et al. (2003). These 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.

Vidal et al. (2004) reported a large 5-generation French family in which
11 members had neuroferritinopathy inherited in an autosomal dominant
pattern. Six affected family members were living at the time of the
report. The proband first developed tremor at age 20 years. Thereafter,
she had a progressive neurologic decline, characterized by frontal and
subcortical cognitive impairment and involuntary movements in her
mid-fifties, and pyramidal signs in her late fifties. She had
dyskinesias, rigidity, hypertonicity, buccolingual dyskinesia, and
dystonic posturing of the hands and feet. She became wheelchair-bound,
was unable to feed herself, and died in a comatose state.
Neuropathologic examination showed cerebellar and cerebral atrophy,
cavitation of the putamen, and widespread ferritin inclusions in neurons
and glia throughout the brain. Ferritin inclusions were also seen in
extraneural tissue, including skin, muscle, and kidney. Serum ferritin
was not measured. Vidal et al. (2004) noted the earlier age at onset in
this family compared to the family reported by Curtis et al. (2001), as
well as the prominent tremor and cognitive decline in the French family.

Maciel et al. (2005) reported a 19-year-old man with parkinsonism,
ataxia, and corticospinal signs consistent with neuroferritinopathy.
Genetic analysis detected a mutation in the FTL gene (A96T; 134790.0013)
in the patient, his asymptomatic mother, and his asymptomatic
13-year-old brother. 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.

Chinnery et al. (2007) reported the clinical features of 41 individuals
with neuroferritinopathy due to a 460insA mutation in the FTL gene
(134790.0010). The mean age of onset was 39.4 years (range, 13-63),
presenting with chorea in 50%, focal lower limb dystonia in 42.5%, and
parkinsonism in 7.5%. Other variable features included writer's cramp,
blepharospasm, and palatal tremor. The disease showed progression over 5
to 10 years, resulting in a generalized disorder with severe asymmetric
motor disability and dystonia, dysphagia, and aphonia, although most
remained ambulatory. None developed overt spasticity, ophthalmologic
changes, or seizures. The majority of patients had normal psychometric
profiles and no cognitive dysfunction except for defects in verbal
fluency, even after 10 years. Two patients had evidence of a
frontal/subcortical dementia after 10 years, but 1 had normal cognition
36 years after onset. Overall, however, many had subtle features of
disinhibition and emotional lability. Five of 6 studied had
mitochondrial chain respiratory defects in skeletal muscle biopsies.
Laboratory studies showed low levels in most males and postmenopausal
females, but normal levels in premenopausal females. Brain imaging
showed iron deposition predominantly in the basal ganglia in all
affected individuals and in 1 presymptomatic carrier. Some with advanced
disease showed cystic degenerative changes. The majority of patients
reported a family history of a movement disorder, which was often
misdiagnosed as Huntington disease, and admission to a psychiatric
institution. Treatment with iron depletion therapy did not provide any
benefit, at least in the short term. Chinnery et al. (2007) concluded
that isolated parkinsonism is unusual in neuroferritinopathy, and that
cognitive changes are absent or subtle in the early stages. Devos et al.
(2009) noted that 3 French patients reported by Chinnery et al. (2007)
were found to carry a different mutation in the FTL gene (458dupA;
134790.0016).

Ohta et al. (2008) reported a Japanese mother and son with
neuroferritinopathy confirmed by genetic analysis (134790.0015). 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, and chorea were not observed. His mother
had hand tremors at age 10, 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.

Keogh et al. (2012) found that 3 asymptomatic descendants of known FTL
mutation carriers who themselves were carriers of a mutation (460insA;
134790.0010) had evidence of iron deposition on brain imaging. In each
case, the signal abnormalities were visible on T2*-weighted MRI. The
abnormalities increased with age: 1 patient between 6 and 16 years had
involvement of the substantia nigra, globus pallidus, and motor cortex;
a patient between 17 and 25 years had additional involvement of the red
nucleus and thalamus, but not the motor cortex; and the third patient,
between 26 and 36 years, had additional involvement of the caudate. The
findings indicated that iron deposition in neuroferritinopathy can begin
decades before symptomatic presentation, and suggested that iron
deposition initiates neurodegeneration.

MAPPING

In a family with adult-onset basal ganglia disease, Curtis et al. (2001)
found linkage to a 3.5-cM region between D19S596 and D19S866 (maximum
multipoint lod score of 6.38 for HRC.PCR3).

MOLECULAR GENETICS

In an individual with adult-onset basal ganglia disease and in 5
apparently unrelated subjects with similar extrapyramidal symptoms,
Curtis et al. (2001) identified an insertion mutation in the FTL gene
(134790.0010). Curtis et al. (2001) proposed a dominant-negative or
dominant gain-of-function effect rather than haploinsufficiency. An
abnormality in ferritin strongly indicated a primary function for iron
in the pathogenesis of this disease, for which they proposed the name
'neuroferritinopathy.'

In affected members of a French family with neuroferritinopathy reported
by Chinnery et al. (2003), Devos et al. (2009) identified a mutation in
the FTL gene (458dupA; 134790.0016). The family had originally been
thought to have a different mutation (134790.0010) (Chinnery et al.,
2003).

Vidal et al. (2004) identified a mutation in the FTL gene (498insTC;
134790.0014) in affected members of a French family with
neuroferritinopathy.

In a healthy 52-year-old woman who was a control subject in a genetic
study of hyperferritinemia-cataract syndrome, 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. She had no history of iron deficiency anemia or neurologic
dysfunction. Hematologic examination was normal except for decreased
serum L-ferritin (615604). The findings suggested that L-ferritin has no
effect on systemic iron metabolism. The report also indicated that
neuroferritinopathy is not a consequence of haploinsufficiency of
L-ferritin, but likely results from gain-of-function mutations in the
FTL gene.

POPULATION GENETICS

In a nationwide survey of Japanese patients, Hirayama et al. (1994)
estimated the prevalence of all forms of spinocerebellar degeneration to
be 4.53 per 100,000. Of these, 1.5% were thought to have striatonigral
degeneration, defined by the authors as a sporadic disorder with onset
after middle age with mainly parkinsonian signs and occasionally
accompanied by cerebellar ataxia, autonomic disturbance, and cerebellar
atrophy on scanning.

NOMENCLATURE

Although some (see, e.g., Chinnery et al., 2007) have referred to
neuroferritinopathy due to FTL mutations as 'neurodegeneration with
brain iron accumulation-2 (NBIA2),' this disorder in OMIM is designated
'NBIA3.' The designation 'NBIA2' is reserved for disorders caused by
mutation in the PLA2G6 gene (603604) on chromosome 22q13 (see NBIA2A,
256600 and NBIA2B, 610217).

*FIELD* RF
1. Chinnery, P. F.; Crompton, D. E.; Birchall, D.; Jackson, M. J.;
Coulthard, A.; Lombes, A.; Quinn, N.; Wills, A.; Fletcher, N.; Mottershead,
J. P.; Cooper, P.; Kellett, M.; Bates, D.; Burn, J.: Clinical features
and natural history of neuroferritinopathy caused by the FTL1 460insA
mutation. Brain 130: 110-119, 2007.

2. Chinnery, P. F.; Curtis, A. R. J.; Fey, C.; Coulthard, A.; Crompton,
D.; Curtis, A.; Lombes, A.; Burn, J.: Neuroferritinopathy in a French
family with late onset dominant dystonia. J. Med. Genet. 40: e69,
2003. Note: Electronic Article.

3. Cremonesi, L.; Cozzi, A.; Girelli, D.; Ferrari, F.; Fermo, I.;
Foglieni, B.; Levi, S.; Bozzini, C.; Camparini, M.; Ferrari, M.; Arosio,
P.: Case report: a subject with a mutation in the ATG start codon
of L-ferritin has no haematological or neurological symptoms. J.
Med. Genet. 41: e81, 2004. Note: Electronic Article.

4. Curtis, A. R. J.; Fey, C.; Morris, C. M.; Bindoff, L. A.; Ince,
P. G.; Chinnery, P. F.; Coulthard, A.; Jackson, M. J.; Jackson, A.
P.; McHale, D. P.; Hay, D.; Barker, W. A.; Markham, A. F.; Bates,
D.; Curtis, A.; Burn, J.: Mutation in the gene encoding ferritin
light polypeptide causes dominant adult-onset basal ganglia disease. Nature
Genet. 28: 350-354, 2001.

5. Devos, D.; Tchofo, P. J.; Vuillaume, I.; Destee, A.; Batey, S.;
Burn, J.; Chinnery, P. F.: Clinical features and natural history
of neuroferritinopathy caused by the 458dupA FTL mutation. (Letter) Brain 132:
e109, 2009. Note: Electronic Article.

6. Gregory, A.; Polster, B. J.; Hayflick, S. J.: Clinical and genetic
delineation of neurodegeneration with brain iron accumulation. J.
Med. Genet. 46: 73-80, 2009.

7. Hirayama, K.; Takayanagi, T.; Nakamura, R.; Yanagisawa, N.; Hattori,
T.; Kita, K.; Yanagimoto, S.; Fujita, M.; Nagaoka, M.; Satomura, Y.;
Sobue, I.; Iizuka, R.; Toyokura, Y.; Satoyoshi, E.: Spinocerebellar
degenerations in Japan: a nationwide epidemiological and clinical
study. Acta Neurol. Scand. 89 (suppl. 153): 1-22, 1994.

8. Keogh, M. J.; Jonas, P.; Coulthard, A.; Chinnery, P. F.; Burn,
J.: Neuroferritinopathy: a new inborn error of iron metabolism. Neurogenetics 13:
93-96, 2012.

9. Maciel, P.; Cruz, V. T.; Constante, M.; Iniesta, I.; Costa, M.
C.; Gallati, S.; Sousa, N.; Sequeiros, J.; Coutinho, P.; Santos, M.
M.: Neuroferritinopathy: missense mutation in FTL causing early-onset
bilateral pallidal involvement. Neurology 65: 603-605, 2005.

10. Ohta, E.; Nagasaka, T.; Shindo, K.; Toma, S.; Nagasaka, K.; Ohta,
K.; Shiozawa, Z.: Neuroferritinopathy in a Japanese family with a
duplication in the ferritin light chain gene. Neurology 70: 1493-1494,
2008.

11. Vidal, R.; Ghetti, B.; Takao, M.; Brefel-Courbon, C.; Uro-Coste,
E.; Glazier, B. S.; Siani, V.; Benson, M. D.; Calvas, P.; Miravalle,
L.; Rascol, O.; Delisle, M. B.: Intracellular ferritin accumulation
in neural and extraneural tissue characterizes a neurodegenerative
disease associated with a mutation in the ferritin light polypeptide
gene. J. Neuropath. Exp. Neurol. 63: 363-380, 2004.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Face];
Orolingual dyskinesia;
Orofacial dystonia;
Oromandibular dyskinesia;
Hypomimia;
[Eyes];
Blepharospasm;
[Mouth];
Palatal tremor

RESPIRATORY:
Pharyngeal dystonia;
[Larynx];
Laryngeal dystonia

ABDOMEN:
[Gastrointestinal];
Dysphagia

SKELETAL:
[Hands];
Writer's cramp;
Micrographia

NEUROLOGIC:
[Central nervous system];
Involuntary movements, asymmetric;
Gait disability;
Parkinsonism;
Bradykinesia;
Tremor;
Extrapyramidal signs;
Choreoathetosis;
Dystonia, focal;
Dysarthria;
Anarthria;
Mutism;
Dysphonia;
Spasticity (less common);
Hyperreflexia;
Extensor plantar responses;
Rigidity;
Cerebellar ataxia;
Cerebellar signs;
Cognitive defects develop later in the disease;
Frontotemporal/subcortical dementia;
Autonomic features may occur;
Neuroaxonal spheroids;
MRI imaging shows cavitation of the basal ganglia;
Brain tissue shows cavitation of the basal ganglia;
Brain tissue shows abnormal spherical aggregates of iron and ferritin
in the basal ganglia, forebrain, and cerebellum;
[Behavioral/psychiatric manifestations];
Disinhibition;
Emotional lability

LABORATORY ABNORMALITIES:
Decreased serum ferritin

MISCELLANEOUS:
Onset 13 to 63 years of age;
Progressive disorder;
Variable phenotype

MOLECULAR BASIS:
Caused by mutation in the ferritin light-chain gene (FTL, 134790.0010)

*FIELD* CN
Cassandra L. Kniffin - updated: 02/19/2010
Cassandra L. Kniffin - updated: 10/31/2005

*FIELD* CD
Cassandra L. Kniffin: 1/26/2005

*FIELD* ED
ckniffin: 02/19/2010
joanna: 12/5/2005
ckniffin: 10/31/2005
ckniffin: 1/26/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 6/13/2012
Cassandra L. Kniffin - updated: 5/14/2007
Cassandra L. Kniffin - updated: 10/31/2005
Cassandra L. Kniffin - reorganized: 9/7/2004

*FIELD* CD
Ada Hamosh: 7/30/2001

*FIELD* ED
carol: 01/15/2014
ckniffin: 1/15/2014
carol: 5/23/2013
alopez: 6/19/2012
ckniffin: 6/13/2012
wwang: 6/10/2011
carol: 4/5/2010
carol: 3/1/2010
ckniffin: 2/19/2010
wwang: 5/16/2007
ckniffin: 5/14/2007
wwang: 11/21/2005
wwang: 11/3/2005
ckniffin: 10/31/2005
ckniffin: 1/26/2005
carol: 9/7/2004
ckniffin: 9/1/2004
alopez: 7/30/2001