NAGLU – Mucopolysaccharidosis type IIIB

N-acetyl-alpha-glucosaminidase (NAGLU) is a lysosomal hydrolase whose deficiency causes mucopolysaccharidosis type IIIB (MPS IIIB), an autosomal recessive disorder marked by heparan sulfate accumulation and progressive neurodegeneration. Affected individuals present in early childhood with behavioral changes, hyperactivity, aggressive behavior, sleep disturbance, and cognitive decline leading to severe disability and early mortality.

Genetic evidence supports autosomal recessive inheritance, with biallelic NAGLU variants in multiple unrelated probands. The initial study of nine fibroblast cell lines identified 10 mutations across nine unrelated patients ([PMID:9443878]) and a subsequent series of 14 patients revealed 16 additional alleles including R297X and R626X ([PMID:9832037]). Segregation of a homozygous exon 3–4 deletion in a consanguineous family ([PMID:20138557]) and confirmation in an elderly sibling pair ([PMID:20040070]) further establish inheritance. Founder alleles such as R565P in Okinawa ([PMID:15933803]) and R234C in the Iberian Peninsula ([PMID:18218046]) illustrate population-specific recurrence.

The variant spectrum comprises over 86 distinct NAGLU mutations—including missense, nonsense, frameshift, splice-site, and small indels—demonstrating loss-of-function as the predominant mechanism ([PMID:11668611]). Recurrent c.889C>T (p.Arg297Ter) accounts for ~12.5% of alleles in Dutch and Australian cohorts ([PMID:11068184]), while hypomorphic alleles such as c.638C>T (p.Pro213Leu) associate with attenuated phenotypes ([PMID:32578945]). The canonical AR pattern and variant heterogeneity support robust genetic evidence for causality.

Functional studies reveal that mutant NAGLU proteins have impaired stability, maturation, and catalytic activity in patient fibroblasts, correlating residual enzyme levels with clinical severity ([PMID:26907177]). Structural analyses of human NAGLU at 2.3 Å resolution map disease-causing residues around the active site and predict destabilizing effects ([PMID:30802506]). In vivo models recapitulate disease hallmarks: a Drosophila Naglu knockout exhibits sex- and age-dependent hyperactivity and neurodegeneration ([PMID:39737777]), and AAV8-mediated delivery of codon-optimized NAGLU in MPS IIIB mice restores enzyme activity, reduces heparan sulfate storage, and corrects neurological deficits ([PMID:35997776]).

Conflicting reports include common polymorphisms p.Ser141Ser and p.Arg737Gly, which do not reduce enzyme activity and likely represent pseudodeficiency alleles ([PMID:31088528]). Variants of uncertain significance require functional validation, as demonstrated by exome-wide activity assays of missense alleles in the ExAC cohort ([PMID:29979746]).

References

• American Journal of Human Genetics • 1998 • NAGLU mutations underlying Sanfilippo syndrome type B. PMID:9443878
• Journal of Medical Genetics • 1998 • Identification of 12 novel mutations in the alpha-N-acetylglucosaminidase gene in 14 patients with Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB). PMID:9832037
• Human Mutation • 2001 • Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. PMID:11668611
• Biochimica et Biophysica Acta • 2000 • Mucopolysaccharidosis type IIIB: characterisation and expression of wild-type and mutant recombinant alpha-N-acetylglucosaminidase and relationship with Sanfilippo phenotype in an attenuated patient. PMID:11068184
• Molecular Genetics and Metabolism • 2010 • Identification and characterization of a novel homozygous deletion in the alpha-N-acetylglucosaminidase gene in a patient with Sanfilippo type B syndrome (mucopolysaccharidosis IIIB). PMID:20138557
• Acta Psychiatrica Scandinavica • 2010 • Sanfilippo B in an elderly female psychiatric patient: a rare but relevant diagnosis in presenile dementia. PMID:20040070
• Journal of Human Genetics • 2005 • Sanfilippo type B syndrome: five patients with an R565P homozygous mutation in the alpha-N-acetylglucosaminidase gene from the Okinawa islands in Japan. PMID:15933803
• Clinical Genetics • 2008 • Molecular analysis of mucopolysaccharidosis type IIIB in Portugal: evidence of a single origin for a common mutation (R234C) in the Iberian Peninsula. PMID:18218046
• Journal of Inherited Metabolic Disease • 2016 • Residual N-acetyl-α-glucosaminidase activity in fibroblasts correlates with disease severity in patients with mucopolysaccharidosis type IIIB. PMID:26907177
• Journal of Structural Biology • 2019 • Structural characterization of the α-N-acetylglucosaminidase, a key enzyme in the pathogenesis of Sanfilippo syndrome B. PMID:30802506
• Genetics • 2025 • A Drosophila model of mucopolysaccharidosis IIIB. PMID:39737777
• Human Molecular Genetics • 2023 • Disease correction in mucopolysaccharidosis type IIIB mice by intraparenchymal or cisternal delivery of a capsid modified AAV8 codon-optimized NAGLU vector. PMID:35997776
• Italian Journal of Pediatrics • 2019 • Polymorphic variants (p.Ser141Ser and p.Arg737Gly) at the NAGLU gene are really indicative of pseudodeficiency alleles? PMID:31088528
• PLoS One • 2018 • Utilizing ExAC to assess the hidden contribution of variants of unknown significance to Sanfilippo Type B incidence. PMID:29979746

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