Multiple Sulfatase Deficiency (MSD)

Multiple Sulfatase Deficiency (MSD) is a rare autosomal recessive disorder in which affected individuals present with a complex phenotype due to the impaired activity of all sulfatases. The lack of sulfatase activities in MSD patients leads to the accumulation of sulfated lipids and carbohydrates resulting in a clinical phenotype that combines the features of at least six diseases due to individual sulfatase deficiencies: metachromatic leukodystrophy (MLD), X-linked ichtyosis, Maroteaux-Lamy syndrome, Hunter syndrome, Sanfilippo A syndrome and Morquio syndrome.

The MSD gene, named Sulfatase Modifying Factor 1 (SUMF1) and encoding the Formylglycine-Generating Enzyme (FGE) is responsible for a post-translational modification of the sulfatases active site required for sulfatases activation (Figure 1).


Figure 1. SUMF1 (Sulfatase Modifying Factor 1) is an essential factor for the activity of all sulfatases.
[Taken From Cosma MP, Pepe S, Annunziata I, Newbold RF, Grompe M, Parenti G, Ballabio A (2003). The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell 113: 445-456].

Coexpression of SUMF1 with sulfatase cDNAs results in a strikingly synergistic increase in enzymatic activity. Thus, SUMF1 is both an essential and a limiting factor for sulfatases and its use is likely to have a considerable impact on enzyme replacement therapy of single sulfatase deficiencies.

Sulfatase activities are completely absent in a mouse line carrying a null mutation in the Sumf1 gene, indicating that Sumf1 is indispensable for sulfatase activation and that mammals, as opposed to bacteria, have a single sulfatase modification system. Likewise MSD patients, Sumf1(-/-) mice display frequent early mortality, congenital growth retardation, skeletal abnormalities, and neurological defects. 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.

MSD is the only disease included in the present project that includes CNS involvement, but the experimental plan proposed will be focused only on the extra neurological manifestation of the disease.

For more details see:
Society for Mucopolysaccharide Diseases

Patient organizations:
Multiple sulfatase deficiency –