Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency

Maria Pia Cosma, Stefano Pepe, Giancarlo Parenti, Carmine Settembre, Ida Annunziata, Richard Wade-Martins, Camela Di Domenico, Paola Di Natale, Anuj Mankad, Barbara Cox, Graziella Uziel, Grazia Mancini, Enrico Zammarchi, Maria Alice Donati, Wim J. Kleijer, Mirella Filocamo, Romeo Carrozzo, Massimo Carella, Andrea Ballabio

Research output: Contribution to journalArticle

Abstract

Multiple sulfatase deficiency (MSD) is a rare disorder characterized by impaired activity of all known sulfatases. The gene mutated in this disease is SUMF1, which encodes a protein involved in a post-translational modification at the catalytic site of all sulfatases that is necessary for their function. SUMF1 strongly enhances the activity of sulfatases when coexpressed with sulfatase in Cos-7 cells. We performed a mutational analysis of SUMF1 in 20 MSD patients of different ethnic origin. The clinical presentation of these patients was variable, ranging from severe neonatal forms to mild phenotypes showing mild neurological involvement. A total of 22 SUMF1 mutations were identified, including missense, nonsense, microdeletion, and splicing mutations. We expressed all missense mutations in culture to study their ability to enhance the activity of sulfatases. Of the predicted amino acid changes, 11 (p.R349W, p.R224W, p.L20F, p.A348P, p.S155P, p.C218Y, p.N259I, p.A279V, p.R349Q, p.C336R, p.A177P) resulted in severely impaired sulfatase-enhancing activity. Two (p.R345C and p.P266L) showed a high residual activity on some, but not all, of the nine sulfatases tested, suggesting that some SUMF1 mutations may have variable effects on the activity of each sulfatase. This study compares, for the first time, clinical, biochemical, and molecular data in MSD patients. Our results show lack of a direct correlation between the type of molecular defect and the severity of phenotype.

Original languageEnglish
Pages (from-to)576-581
Number of pages6
JournalHuman Mutation
Volume23
Issue number6
DOIs
Publication statusPublished - May 2004

Fingerprint

Multiple Sulfatase Deficiency Disease
Sulfatases
Mutation
Phenotype
Missense Mutation
Post Translational Protein Processing
Catalytic Domain

Keywords

  • Clinical presentation
  • MSD
  • Multiple sulfatase deficiency
  • Mutation analysis
  • SUMF1

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Cosma, M. P., Pepe, S., Parenti, G., Settembre, C., Annunziata, I., Wade-Martins, R., ... Ballabio, A. (2004). Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Human Mutation, 23(6), 576-581. https://doi.org/10.1002/humu.20040

Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. / Cosma, Maria Pia; Pepe, Stefano; Parenti, Giancarlo; Settembre, Carmine; Annunziata, Ida; Wade-Martins, Richard; Di Domenico, Camela; Di Natale, Paola; Mankad, Anuj; Cox, Barbara; Uziel, Graziella; Mancini, Grazia; Zammarchi, Enrico; Donati, Maria Alice; Kleijer, Wim J.; Filocamo, Mirella; Carrozzo, Romeo; Carella, Massimo; Ballabio, Andrea.

In: Human Mutation, Vol. 23, No. 6, 05.2004, p. 576-581.

Research output: Contribution to journalArticle

Cosma, MP, Pepe, S, Parenti, G, Settembre, C, Annunziata, I, Wade-Martins, R, Di Domenico, C, Di Natale, P, Mankad, A, Cox, B, Uziel, G, Mancini, G, Zammarchi, E, Donati, MA, Kleijer, WJ, Filocamo, M, Carrozzo, R, Carella, M & Ballabio, A 2004, 'Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency', Human Mutation, vol. 23, no. 6, pp. 576-581. https://doi.org/10.1002/humu.20040
Cosma MP, Pepe S, Parenti G, Settembre C, Annunziata I, Wade-Martins R et al. Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Human Mutation. 2004 May;23(6):576-581. https://doi.org/10.1002/humu.20040
Cosma, Maria Pia ; Pepe, Stefano ; Parenti, Giancarlo ; Settembre, Carmine ; Annunziata, Ida ; Wade-Martins, Richard ; Di Domenico, Camela ; Di Natale, Paola ; Mankad, Anuj ; Cox, Barbara ; Uziel, Graziella ; Mancini, Grazia ; Zammarchi, Enrico ; Donati, Maria Alice ; Kleijer, Wim J. ; Filocamo, Mirella ; Carrozzo, Romeo ; Carella, Massimo ; Ballabio, Andrea. / Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. In: Human Mutation. 2004 ; Vol. 23, No. 6. pp. 576-581.
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