Systemic inflammation and neurodegeneration in a mouse model of multiple sulfatase deficiency

Carmine Settembre, Ida Annunziata, Carmine Spampanato, Daniela Zarcone, Gilda Cobellis, Edoardo Nusco, Ester Zito, Carlo Tacchetti, Maria Pia Cosma, Andrea Ballabio

Research output: Contribution to journalArticlepeer-review


Sulfatases are involved in several biological functions such as degradation of macromolecules in the lysosomes. In patients with multiple sulfatase deficiency, mutations in the SUMF1 gene cause a reduction of sulfatase activities because of a posttranslational modification defect. We have generated a mouse line carrying a null mutation in the Sumf1 gene. Sulfatase activities are completely absent in Sumf1-/- mice, indicating that Sumf1 is indispensable for sulfatase activation and that mammals, differently from bacteria, have a single sulfatase modification system. Similarly to multiple sulfatase deficiency patients, Sumf1-/- mice display frequent early mortality, congenital growth retardation, skeletal abnormalities, and neurological defects. All examined tissues showed progressive cell vacuolization and significant lysosomal storage of glycosaminoglycans. Sumf1-/- mice showed a generalized inflammatory process characterized by a massive presence of highly vacuolated macrophages, which are the main site of lysosomal storage. Activated microglia were detected in the cerebellum and brain cortex associated with remarkable astroglyosis and neuronal cell loss. Between 4 and 6 months of age, we detected a strong increase in the expression levels of inflammatory cytokines and of apoptotic markers in both the CNS and liver, demonstrating that inflammation and apoptosis occur at the late stage of disease and suggesting that they play an important role in both the systemic and CNS phenotypes observed in lysosomal disorders. This mouse model, in which the function of an entire protein family has been silenced, offers a unique opportunity to study sulfatase function and the mechanisms underlying lysosomal storage diseases.

Original languageEnglish
Pages (from-to)4506-4511
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number11
Publication statusPublished - Mar 13 2007


  • Apoptosis
  • Macrophages
  • Sulfatase modifying factor 1

ASJC Scopus subject areas

  • Genetics
  • General


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