Neuroferritinopathy in a Japanese Family With a Duplication in the Ferritin Light Chain Gene

Ohta, Emiko; Nagasaka, Takamura; Shindo, Kazumasa; Toma, S.; Nagasaka, Kaori; Ohta, Kazuaki; Shiozawa, Zenji

doi:10.1212/01.wnl.0000310428.74624.95

Cited by 58 publications

(44 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hereditary ferritinopathies have similar phenotypic expressions, with brain iron accumulation, movement disorders, and the formation of ferritin bodies in the brain and other tissues (15,16,45). However, the ferritin mutations associated with the disorders are rather different: they modify different lengths of the C terminus, and one-or two-nucleotide frameshifts produce different sequences with extensions of 4 or 16 residues.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mutant Ferritin L-chains That Cause Neurodegeneration Act in a Dominant-negative Manner to Reduce Ferritin Iron Incorporation

Luscieti

Santambrogio

d’Estaintot

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

“…Six pathogenic mutations have been identified so far (9,10,(12)(13)(14)(15)(16). They are all private mutations found in single families, except the 460InsA found in several patients of North Anglia.…”

mentioning

confidence: 99%

Mutant Ferritin L-chains That Cause Neurodegeneration Act in a Dominant-negative Manner to Reduce Ferritin Iron Incorporation

Luscieti

Santambrogio

d’Estaintot

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…Seven pathogenic mutations in FTL1 have since been described [1][2][3][4][5][6][7]. Six are frameshift mutations which alter the reading frame and are predicted to extend the ferritin light chain peptide at the site of the pore in the ferritin molecule.…”

Section: Introductionmentioning

confidence: 99%

Neuroferritinopathy: a new inborn error of iron metabolism

Keogh

Jonas

Coulthard³

et al. 2012

Neurogenetics

View full text Add to dashboard Cite

Neuroferritinopathy is an autosomal dominant progressive movement disorder which occurs due to mutations in the ferritin light chain gene (FTL1). It presents in mid-adult life and is the only autosomal dominant disease in a group of conditions termed neurodegeneration with brain iron accumulation (NBIA). We performed brain MRI scans on 12 asymptomatic descendants of known mutation carriers. All three harbouring the pathogenic c.460InsA mutation showed iron deposition; these findings show pathological iron accumulation begins in early childhood which is of major importance in understanding and developing treatment for NBIA.

show abstract

“…In humans, nucleotide insertions in the coding sequence of the ferritin light chain (FTL) 4 gene (1)(2)(3)(4)(5)(6) are associated with an autosomal dominant neurodegenerative disease named neuroferritinopathy (1) or hereditary ferritinopathy (HF) (2,7). Clinically, HF is characterized by an abnormal involuntary movement disorder and cognitive decline.…”

mentioning

confidence: 99%

Unraveling of the E-helices and Disruption of 4-Fold Pores Are Associated with Iron Mishandling in a Mutant Ferritin Causing Neurodegeneration

Baraibar¹,

Muhoberac

Garringer³

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Mutations in the coding sequence of the ferritin light chain (FTL) gene cause a neurodegenerative disease known as neuroferritinopathy or hereditary ferritinopathy, which is characterized by the presence of intracellular inclusion bodies containing the mutant FTL polypeptide and by abnormal accumulation of iron in the brain. Here, we describe the x-ray crystallographic structure and report functional studies of ferritin homopolymers formed from the mutant FTL polypeptide p.Phe167SerfsX26, which has a C terminus that is altered in amino acid sequence and length. The structure was determined and refined to 2.85 Å resolution and was very similar to the wild type between residues Ile-5 and Arg-154. However, instead of the E-helices normally present in wild type ferritin, the C-terminal sequences of all 24 mutant subunits showed substantial amounts of disorder, leading to multiple C-terminal polypeptide conformations and a large disruption of the normally tiny 4-fold axis pores. Functional studies underscored the importance of the mutant C-terminal sequence in iron-induced precipitation and revealed iron mishandling by soluble mutant FTL homopolymers in that only wild type incorporated iron when in direct competition in solution with mutant ferritin. Even without competition, the amount of iron incorporation over the first few minutes differed severalfold. Our data suggest that disruption at the 4-fold pores may lead to direct iron mishandling through attenuated iron incorporation by the soluble form of mutant ferritin and that the disordered C-terminal polypeptides may play a major role in iron-induced precipitation and formation of ferritin inclusion bodies in hereditary ferritinopathy.

show abstract

Neuroferritinopathy in a Japanese Family With a Duplication in the Ferritin Light Chain Gene

Cited by 58 publications

References 7 publications

Mutant Ferritin L-chains That Cause Neurodegeneration Act in a Dominant-negative Manner to Reduce Ferritin Iron Incorporation

Mutant Ferritin L-chains That Cause Neurodegeneration Act in a Dominant-negative Manner to Reduce Ferritin Iron Incorporation

Neuroferritinopathy: a new inborn error of iron metabolism

Unraveling of the E-helices and Disruption of 4-Fold Pores Are Associated with Iron Mishandling in a Mutant Ferritin Causing Neurodegeneration

Contact Info

Product

Resources

About