Study of FTMT and ABCA4 genes in a patient affected by age-related macular degeneration: Identification and analysis of new mutations

Stefania Stenirri, Paolo Santambrogio, Marco Setaccioli, Benedetta Gaia Erba, Maria Pia Manitto, Ermanna Rovida, Maurizio Ferrari, Sonia Levi, Laura Cremonesi

Research output: Contribution to journalArticlepeer-review


Background: Age-related macular degeneration (AMD) is a multifactorial disease for which an involvement of alterations in the retinal ABC transporter gene (ABCA4) is still debated. Oxidative stress in retinal pigment epithelial cells has been postulated to contribute to the pathogenesis of the disease. Mitochondrial ferritin (FtMt), an iron-sequestering protein, is expressed in cell types characterized by high metabolic activity and oxygen consumption, including human retina, suggesting a role in protecting mitochondria from irondependent oxidative damage. Based on these findings we wanted to investigate whether mutations in this gene could be found in AMD patients. Methods: Mutational scanning of the FTMT gene was performed in a cohort of 50 patients affected by age-related macular degeneration. The ABCA4 gene was also scanned in one patient carrying an FtMt mutation. In silico analyses were carried out on the identified variants. The recombinant form of FtMt variant was expressed in Escherichia coli and biochemically characterized. Results: One patient was found to be heterozygous for two previously unreported genetic changes: a complex FtMt mutation (c.437-450delinsCT: delAGGACATCAAGAAGinsCT) and a missense p.Leu973Phe (c.2919G > T) mutation in exon 20 of ABCA4. Computational analyses predicted a severe structural impairment for FtMt variant and a mild destabilizing effect for ABCA4. E. coli expression of recombinant FtMt variant yielded a highly insoluble protein that could not be renatured under in vitro conditions suitable for wild-type ferritins. Conclusions: Our findings suggest that the FtMt mutation may determine a condition similar to haploinsufficiency resulting in a reduced protection from iron-dependent oxidative stress in mitochondria.

Original languageEnglish
Pages (from-to)1021-1029
Number of pages9
JournalClinical Chemistry and Laboratory Medicine
Issue number6
Publication statusPublished - Jun 2012


  • ABCA4
  • Age-related macular degeneration
  • Mitochondrial ferritin

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Biochemistry, medical


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