Back to Search Start Over

SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies

Authors :
Andrea Ballabio
Alessandro Fraldi
Edoardo Nusco
Alessia Lombardi
Luigi Naldini
Alessandra Biffi
Maria Pia Cosma
Ilaria Visigalli
Alberto Auricchio
Carmine Settembre
Stefano Pepe
Fraldi, A
Biffi, A
Lombardi, A
Visigalli, I
Pepe, S
Settembre, C
Nusco, E
Auricchio, A
Naldini, Luigi
Ballabio, A
Cosma, Mp
TIGEM (Telethon Institute of Genetics and Medicine)
Telethon Institute of Genetics and Medicine = Istituto Telethon di Genetica e Medicina (TIGEM)
Fraldi, Alessandro
A., Biffi
A., Lombardi
I., Visigalli
S., Pepe
Settembre, Carmine
E., Nusco
Auricchio, Alberto
L., Naldini
Ballabio, Andrea
M. P. C. o. s. m., A.
Source :
Biochemical Journal, Biochemical Journal, Portland Press, 2007, 403 (2), pp.305-312. ⟨10.1042/BJ20061783⟩
Publication Year :
2007
Publisher :
Portland Press Ltd., 2007.

Abstract

Sulfatases are enzymes that hydrolyse a diverse range of sulfate esters. Deficiency of lysosomal sulfatases leads to human diseases characterized by the accumulation of either GAGs (glycosaminoglycans) or sulfolipids. The catalytic activity of sulfatases resides in a unique formylglycine residue in their active site generated by the post-translational modification of a highly conserved cysteine residue. This modification is performed by SUMF1 (sulfatase-modifying factor 1), which is an essential factor for sulfatase activities. Mutations in the SUMF1 gene cause MSD (multiple sulfatase deficiency), an autosomal recessive disease in which the activities of all sulfatases are profoundly reduced. In previous studies, we have shown that SUMF1 has an enhancing effect on sulfatase activity when co-expressed with sulfatase genes in COS-7 cells. In the present study, we demonstrate that SUMF1 displays an enhancing effect on sulfatases activity when co-delivered with a sulfatase cDNA via AAV (adeno-associated virus) and LV (lentivirus) vectors in cells from individuals affected by five different diseases owing to sulfatase deficiencies or from murine models of the same diseases [i.e. MLD (metachromatic leukodystrophy), CDPX (X-linked dominant chondrodysplasia punctata) and MPS (mucopolysaccharidosis) II, IIIA and VI]. The SUMF1-enhancing effect on sulfatase activity resulted in an improved clearance of the intracellular GAG or sulfolipid accumulation. Moreover, we demonstrate that the SUMF1-enhancing effect is also present in vivo after AAV-mediated delivery of the sulfamidase gene to the muscle of MPSIIIA mice, resulting in a more efficient rescue of the phenotype. These results indicate that co-delivery of SUMF1 may enhance the efficacy of gene therapy in several sulfatase deficiencies.

Details

ISSN :
14708728 and 02646021
Volume :
403
Database :
OpenAIRE
Journal :
Biochemical Journal
Accession number :
edsair.doi.dedup.....48d791beefbb57c935bd592c929bc5e2
Full Text :
https://doi.org/10.1042/bj20061783