Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications

Mucopolysaccharidosis (MPS) types IIIA, B, C, and D are a group of autosoma l recessive lysosomal storage diseases caused by mutations in one of four g enes which encode enzyme activities required for the lysosomal. degradation of heparan sulfate. The progressive lysosomal storage of heparan sulfate e ventually results in the clinical onset of disease, which is predominantly characterized by severe central nervous system degeneration. MPS-IIIA and M PS-IIIB involve deficiencies of heparan sulfate sulfamidase (SGSH) and alph a -N-acetylglucosaminidase (NAGLU), respectively. Both the SGSH and NAGLU g enes have been cloned and characterized, thereby permitting mutation analys is of MPS-IIIA and MPS-IIIB patients. A total of 62 mutations have now been defined for MPS-IIIA consisting of 46 missense/nonsense mutations, 15 smal l insertions/deletions, and one splice site mutation. A total of 86 mutatio ns have been identified in the NAGLU gene of MPS-IIIB patients; 58 missense /nonsense mutations, 27 insertions/deletions, and one splice site mutation. Most of the identified mutations in the SGSH and NAGLU genes are associate d with severe clinical phenotypes. Many of the missense, nonsense, and inse rtion/delction mutations have been expressed in mammalian cell lines to per mit the characterization of their effects on SGSH and NAGLU activity and in tracellular processing and trafficking. For MPS-IIIA and MPS, IIIB many of the reported mutations are unique making screening the general population d ifficult. However, molecular characterization of MPS-IIIA patients has reve aled a high incidence of particular mutations of different geographical ori gins, which will be beneficial for the molecular diagnosis of MPS-IIIA. Hum Mutat 18:264-281, 2001. (C) 2001 Wiley-Liss, Inc.