FTL

Chr 19ADAR

ferritin light chain

Also known as: FTL1, LFTD, NBIA3

NCBI Gene: 2512 ENSG00000087086 UniProt: P02792 OMIM: 134790

The light subunit of ferritin stores iron in a soluble and nontoxic state within cells, with subunit composition affecting iron uptake and release rates across tissues. Mutations cause hyperferritinemia-cataract syndrome, L-ferritin deficiency, and neurodegeneration with brain iron accumulation type 3 through both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves dominant-negative effects where mutant protein disrupts normal ferritin function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes the light subunit of the ferritin protein. Ferritin is the major intracellular iron storage protein in prokaryotes and eukaryotes. It is composed of 24 subunits of the heavy and light ferritin chains. Variation in ferritin subunit composition may affect the rates of iron uptake and release in different tissues. A major function of ferritin is the storage of iron in a soluble and nontoxic state. Defects in this light chain ferritin gene are associated with several neurodegenerative diseases and hyperferritinemia-cataract syndrome. This gene has multiple pseudogenes. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 1.953 OMIM phenotypes

Clinical Summary— FTL

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Gene-Disease Validity (ClinGen)

hereditary hyperferritinemia with congenital cataracts · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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GeneReview available — FTL

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.95LOEUF

pLI 0.000

Z-score -1.51

OE 1.62 (0.96–1.95)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.44Z-score

OE missense 1.13 (0.96–1.33)

106 obs / 94.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.62 (0.96–1.95)

0≤0.351.4

Missense OE?1.13 (0.96–1.33)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 11 / 6.8Missense obs/exp: 106 / 94.0Syn Z: 0.06

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveFTL-related hereditary hyperferritinemia-cataract syndromeLOFAD

This gene — mechanism propensity

0.7132th %ile

GOF

0.6246th %ile

LOF

0.2970th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNActing in a dominant negative manner, mutations are responsible for an impairment of the iron storage efficiency of ferritin molecule.1

LOFWe conclude that haploinsufficiency of FTL may be associated with hypoferritinemia without neurological dysfunction.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References