Mucopolysaccharidosis III: Molecular genetics and genotype- phenotype correlations

Introduction Sanfilippo Syndrome or Mucopolysaccharidosis III (MPS III) is a group of lysosomal storage diseases resulting from a deficiency of one of four lysosomal enzymes: Type A heparan N-sulfatase (SGSH), Type B α-N-acetylglucosaminidase (NAGLU), Type C acetyl CoA α-glucosaminide acetyltransferase (HGSNAT) and Type D N-acetylglucosamine-6-sulfatase (GNS). Each of these enzymes is necessary for degradation of heparan sulphate. Deficiency of any of these enzymes manifests as a neurodegenerative disorder with accompanying somatic manifesttations. Currently treatment is limited to supportive care. MPS IIIA and IIIB are the most common subtypes of MPS III and will be further discussed in this review. The integral genes underlying both these diseases have been cloned and characterized. Through genetic analysis of the cDNA from MPS IIIA and B, researchers have begun to link many genetic mutations to their resultant phenotypes, and discern geographic differences in mutational variation. Here, we highlight many of the known MPS IIIA and B mutations and present them in the context of ethnic and geographic differences in an attempt to discern genotype-phenotype correlations and patterns of inheritance. Conclusion Most mutation sites have variable severity. A few sites have predictably more or less acute disease courses but all described mutations still result in progressive neurodegeneration and premature death. Introduction Mucopolysaccharidoses are a group of eleven inherited lysosomal storage diseases (LSDs) resulting from a particular enzyme deficiency. Sanfilippo Syndrome, commonly referred to as Mucopolysaccharidosis III (MPS III), results from a deficiency in one of four lysosomal enzymes needed to break down heparan sulfate (HS). Heparan sulphate functions biologically as a proteoglycan which occurs as cell-surface and extracellular matrix macromolecules. These proteoglycans play crucial roles in regulating key developmental signalling pathways by binding to specific protein ligands and in maintaining cellular homeostasis. MPS III is inherited in an autosomal recessive manner and each of the four enzyme deficiencies defines a particular type of MPS III. Namely, Type A heparan N-sulphatase (SGSH, OMIM # 252900), Type B α-Nacetylglucosaminidase (NAGLU, OMIM # 2529520), Type C acetyl CoA αglucosaminide acetyltransferase (HGSNAT, OMIM # 252930) and Type D N-acetylglucosamine-6-sulfatase (GNS, OMIM # 252940). Deficiency of any of these enzymes manifests as a neurodegenerative disorder with accompanying somatic manifesttations. Of the mucopolysaccharidoses, MPS III is the most frequent, with an estimated incidence of 0.28 4.1 per 100,000 persons1. MPS IIIA and -B, are the most common subtypes of MPS III2,3 and will be further discussed in this review. The cDNA sequences for SGSH4 and NAGLU5,6 have been cloned and characterized, with gene locations on chromosomes 17q25.3 and 17q21.2, respectively. The SGSH sequence contains eight exons which span approximately 11 kb and encodes a 502 amino acid protein with five potential N-glycosylation sites located at positions 41, 142, 151, 264 and 413 (neXtProt, NX_P51688). Whereas, the NAGLU sequence contains six exons which span approximately 8.3 kb and encodes a 743 amino acid protein consisting of a 20to 23residue sequence considered to be the signal peptide and six potential Nglycosylation sites located at positions 261, 272, 435, 503, 526 and 532 (neXtProt, NX_P54802). Once synthesized, these enzymes are shuttled to the trans-golgi network where mannose-6-phosphate (M6P) modifications are added and serve as ligands to interact with M6P receptors. This interaction allows lysosomal enzymes to be segregated from other proteins and transported to lysosomes under normal conditions. The aim of this review is to aggregate and synthesize retrospective genetic analysis data on MPS IIIA and –IIIB with the goal of highlighting genotypephenotype correlations and clinical predictive patterns associated with disease severity.