Alternative titles; symbols
HGNC Approved Gene Symbol: NAGLU
SNOMEDCT: 1187618009, 59990008; ICD10CM: E76.22;
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38) : 17:42,536,241-42,544,449 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.2 | ?Charcot-Marie-Tooth disease, axonal, type 2V | 616491 | Autosomal dominant | 3 |
| Mucopolysaccharidosis type IIIB (Sanfilippo B) | 252920 | Autosomal recessive | 3 |
Zhao et al. (1995) and Zhao et al. (1996) cloned a cDNA corresponding to alpha-N-acetylglucosaminidase, which they symbolized NAGLU. The deduced 743-amino acid protein has a 20- to 23-residue leader sequence, consistent with a signal peptide, and 6 potential N-glycosylation sites. The mature protein contains 720 amino acids and has a molecular mass of approximately 80 kD.
Weber et al. (1996) reported the cloning of the NAGLU gene by enzyme protein purification, amino acid sequence determination, and database searches. A TFASTA search aligned the amino acid sequence to sequence in the 5-prime flanking region of the 17-beta-hydroxysteroid dehydrogenase-1 gene (HSD17B1; 109684), and this sequence was used to screen cDNA libraries. Northern blot analysis showed a single 2.7-kb mRNA transcript with high expression levels in liver, ovary, and peripheral blood leukocytes and measurable amounts of transcript in other tissues. The full-length cDNA sequence was cloned into an expression vector, and cultured CHO cells transfected with this vector showed a 17-fold increase in enzyme expression.
Zhao et al. (1996) determined that the NAGLU gene contains 6 exons and spans 8.3 kb.
Zhao et al. (1996) mapped the NAGLU gene to chromosome 17q21. The 3-prime end of NAGLU resides in the upstream flanking region of the HSD17B1 gene.
Vance et al. (1980) demonstrated variable alpha-N-acetylglucosaminidase activity levels among different groups of normal control populations, indicating polymorphisms within the gene that encodes the enzyme. Pericak-Vance et al. (1985) confirmed the polymorphisms reported by Vance et al. (1980) in studies of a large black kindred. They pointed out that alleles for high and low NAG enzyme activity might confuse the identification of heterozygotes. The mean values for NAG activity of the 3 genotypes varied in black and in white groups. Thermal stability data were cited suggesting that structurally distinct allelic forms of the enzyme may be segregating in the 2 racial groups.
Mucopolysaccharidosis, Type IIIB
Using SSCP analysis of PCR-amplified segments of genomic DNA from patients with Sanfilippo syndrome B, also known as mucopolysaccharidosis IIIB (MPS3B; 252920), Zhao et al. (1996) identified several recessive mutations in the NAGLU gene (see, e.g., 609701.0001-609701.0005). All missense mutations occurred at CpG sites, known to be mutagenic hotspots.
Zhao et al. (1998) stated that 36% of all known point mutations in the NAGLU gene causing MPS IIIB (8 of 22 alleles) involve arginine-674 (see, e.g., 609701.0001), a codon having a CpG dinucleotide in the critical initial position.
In 9 fibroblast cell lines of Sanfilippo syndrome B patients, Schmidtchen et al. (1998) identified 10 additional mutations in the NAGLU gene. Functional expression studies showed that the mutant enzymes had no residual activity. Nine of the 10 amino acid substitutions that had been identified to that time clustered near the amino or the carboxy end of the enzyme, suggesting a role for these regions in the transport or function of the protein.
Beesley et al. (1998) identified 12 novel mutations in the NAGLU gene in 14 patients with MPS IIIB. Bunge et al. (1999) identified 21 mutations, including 18 novel mutations, in the NAGLU gene in 22 patients with MPS IIIB. The mutation spectrum consisted of 2 small insertions, 2 small deletions, 3 nonsense mutations, and 14 different missense mutations, 1 of which affected the initiation codon.
In a study of 40 patients with Sanfilippo syndrome B, most of them of Australasian and Dutch origin, Weber et al. (1999) identified 31 mutations, 25 of them novel, and 2 polymorphisms in the NAGLU gene. The observed allelic heterogeneity reflected the wide spectrum of clinical phenotypes reported for these patients. Most of the changes were missense mutations; 4 nonsense and 9 frameshift mutations caused by insertions or deletions were also identified. Only 5 mutations were found in more than 1 patient. R643C (609701.0006) and R297X (609701.0003) each accounted for approximately 20% of MPS IIIB alleles in the Dutch patient group, while R297X, P521L (609701.0007), R565W (609701.0008), and R626X (609701.0002) each had a frequency of about 6% in Australasian patients. R643C seemed to be a Dutch MPS IIIB allele and clearly conferred an attenuated phenotype. One region of the gene showed a higher concentration of mutations, probably reflecting the instability of this area which contains a direct repeat. Several arginine residues seemed to be hotspots for mutations, being affected by 2 or 3 individual basepair exchanges (see 609701.0004 and 609701.0006).
In a mutation screen of 20 patients with Sanfilippo syndrome B, Tessitore et al. (2000) identified 28 mutations, 14 of which were novel, in the NAGLU gene. Of these mutations, 4 were found in homozygosity and only 1 was seen in 2 different patients, showing the remarkable molecular heterogeneity of the disorder.
Yogalingam and Hopwood (2001) reported that 86 new mutations had been identified in the NAGLU gene in MPS IIIB patients: 58 missense/nonsense mutations, 27 insertion/deletions, and 1 splice site mutation. All mutations were associated with severe clinical phenotypes.
Tanaka et al. (2002) performed molecular analysis of the NAGLU gene in 7 Japanese patients with Sanfilippo syndrome type B from 6 unrelated families; 6 disease-causing mutations were found, of which 2 were novel. Two families were from Okinawa, where more patients with Sanfilippo syndrome were found than in other areas in Japan. Two sibs, who were compound heterozygous for F314L (609701.0011) and R565P (609701.0009), showed an attenuated form. Two patients with a severe phenotype with rapid progression were homozygous for R482W (609701.0012) and R565P, respectively. Tanaka et al. (2002) suggested that the R565P mutation is common in Okinawa. Chinen et al. (2005) identified the homozygous R565P mutation in 5 unrelated Japanese patients from Okinawa, suggesting a founder effect.
Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. They identified a family (8600486) in which 3 of 4 children, born to parents related as first cousins once removed, had MPS IIIB (severe intellectual disability, autism spectrum disorder, and coarse facial features) and a homozygous missense mutation in the NAGLU gene (609701.0014).
Charcot-Marie-Tooth Disease, Axonal, Type 2V
In affected members of a large French Canadian kindred with autosomal dominant axonal Charcot-Marie-Tooth disease type 2V (CMT2V; 616491), Tetreault et al. (2015) identified a heterozygous missense mutation in the NAGLU gene (I403T; 609701.0015). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Patient leukocytes showed significantly decreased NAGLU enzyme activity (36-54% of controls), consistent with a detrimental effect of the mutation. The patients had adult onset of progressive lower leg pain and distal sensory impairment.
In the study of Weber et al. (1999), all mutations resulting in premature termination either by a nonsense mutation or frameshift insertions and deletions led to the severe phenotype. Similarly, deletions masking the normal stop codon and presumably elongating the gene product conferred a severe phenotype when in combination with R297X. Missense mutations V334F and P521L also caused the severe phenotype when present on both alleles in individual patients. Most of the Dutch patients showed clinical symptoms consistent with the attenuated form of the disease. Two patients were diagnosed at the age of 63 and 47 years, respectively. Two of the attenuated cases, who were apparently not related, were found to be homozygous for R643C, an allele that was also identified in an attenuated patient with an unknown second allele. Two patients with R297X in combination with an unknown genotype (compound heterozygotes) had the severe and attenuated phenotype, respectively, implying that the unknown alleles modified the severity of the clinical phenotype.
Li et al. (1999) found that Naglu-deficient mice were healthy and fertile while young and could survive for 8 to 12 months. They were totally deficient in alpha-N-acetylglucosaminidase and had massive accumulation of heparan sulfate in liver and kidney, as well as secondary changes in activity of several other lysosomal enzymes in liver and brain and elevation of gangliosides GM2 and GM3 in brain. Vacuolation was seen in many cells, including macrophages, epithelial cells, and neurons, and became more prominent with age. Although most vacuoles contained finely granular material characteristic of glycosaminoglycan accumulation, large pleiomorphic inclusions were seen in some neurons and pericytes in the brain. Abnormal hypoactive behavior was manifested by 4.5-month-old Naglu -/- mice in an open field test; the hyperactivity that is characteristic of affected children was not observed even in younger mice. In a pavlovian fear conditioning test, the 4.5-month-old mutant mice showed normal response to context, indicating intact hippocampal-dependent learning, but reduced response to a conditioning tone, perhaps attributable to hearing impairment. The phenotype of the deficient mice was considered sufficiently similar to that of patients with Sanfilippo syndrome B to make these mice a good model for study of pathophysiology and for development of therapy.
In mouse models, Ohmi et al. (2003) investigated the implications of microglial involvement for the pathogenesis as well as the potential treatment of MPS I (see 607014) and MPS IIIB. Their investigation showed an inflammatory component of brain disease in both disorders, as is known for many neurodegenerative disorders.
Ryazantsev et al. (2007) performed a detailed study of the brain pathology in mice deficient for the Naglu gene developed by Li et al. (1999). In contrast to somatic cells, which accumulate primarily heparan sulfate, neurons accumulate a number of apparently unrelated metabolites, including subunit c of mitochondrial ATPase synthase (SCMAS). SCMAS accumulated from 1 month of age, primarily in the medial entorhinal cortex and layer V of the somatosensory cortex. Its accumulation was not due to the absence of specific proteases. Light microscopy of brain sections of 6-month-old mice showed SCMAS to accumulate in the same organelles as Lamp1 (153330) and Lamp2 (309060). Cryoimmunoelectron microscopy showed SCMAS to be present in Lamp-positive vesicles bounded by a single membrane (lysosomes), in fingerprint-like layered arrays. GM3 ganglioside was also seen in lysosomes of microglia, suggesting phagocytosis of neuronal membranes. Samples used for cryoelectron microscopy and further processed by standard electron microscopy procedures showed the disappearance of the SCMAS fingerprint arrays and appearance in the same location of 'zebra bodies,' well known but little understood inclusions in the brain of patients with mucopolysaccharidosis.
In 2 Arab patients with Sanfilippo B syndrome, or mucopolysaccharidosis type IIIB (MPS3B; 252920), Zhao et al. (1996) identified a homozygous 2021G-A transition in the NAGLU gene, resulting in an arg674-to-his (R674H) substitution.
In a cell line (GM156) from a patient with Sanfilippo syndrome B (MPS3B; 252920) from the Human Genetic Mutant Cell Repository, Zhao et al. (1996) identified a homozygous 1876C-T transition in the NAGLU gene, resulting in an arg626-to-ter (R626X) substitution.
In a cell line (GM156) from a patient with Sanfilippo syndrome B (MPS3B; 252920) from the Human Genetic Mutant Cell Repository, Zhao et al. (1996) identified compound heterozygosity for 2 mutations in the NAGLU gene: an 889C-T transition, resulting in an arg297-to-ter (R297X) substitution, and a G-to-A transition, resulting in an arg643-to-his (R643H; 609701.0004) substitution.
Weber et al. (1999) found that the R297X mutation was the most common mutation in a cohort of Dutch and Australasian MPS IIIB patients, occurring at a frequency of 12.5%. Yogalingam et al. (2000) found that this mutation was associated with very low levels of NAGLU activity and 12-fold elevations of 35-S-labeled GAG storage when compared with normal fibroblasts.
For discussion of the arg643-to-his (R643H) mutation in the NAGLU gene that was found in compound heterozygous state in a cell line (GM156) from a patient with Sanfilippo syndrome B (MPS3B; 252920) by Zhao et al. (1996), see 609701.0003.
Weber et al. (1999) reported that an R643C mutation (609701.0006) accounted for approximately 20% of MPS3B alleles in a Dutch patient group, suggesting that this arginine residue is a hotspot for mutations.
In cell line from a patient with Sanfilippo syndrome B (MPS3B; 252920), Zhao et al. (1996) found homozygosity for a 10-bp deletion in the NAGLU gene beginning at nucleotide 503; the deletion resulted in a frameshift and predicted termination 14 codons later. The deletion occurs at a direct repeat of a tetranucleotide, GGAG, and may be the result of slipped mispairing during DNA replication.
Weber et al. (1999) reported that an arg643-to-cys (R643C) missense mutation in the NAGLU gene accounted for approximately 20% of mucopolysaccharidosis type IIIB (MPS3B; 252920) alleles in a Dutch patient group. Arginine-643 appears to be a hotspot for mutations; see R643H (609701.0004).
Weber et al. (1999) found that a pro521-to-leu (P521L) missense mutation in the NAGLU gene accounted for approximately 6% of mutations in Australasian patients with Sanfilippo syndrome B (MPS3B; 252920).
Weber et al. (1999) found that an arg565-to-trp (R565W) missense mutation accounted for approximately 6% of the mutant alleles in Australasian patients with Sanfilippo syndrome B (MPS3B; 252920).
Weber et al. (1999) observed an arg565-to-pro (R565P) mutation of the NAGLU gene in compound heterozygous state in a patient with Sanfilippo syndrome B (MPS3B; 252920). The arginine-565 residue appears to be a hotspot for mutations; see 609701.0008.
Tanaka et al. (2002) identified the R565P mutation in homozygous state in a patient with a severe form of Sanfilippo syndrome B. Tanaka et al. (2002) suggested that the R565P mutation may be common in Okinawa.
Chinen et al. (2005) identified the homozygous R565P mutation in 5 unrelated Japanese patients with Sanfilippo syndrome B, suggesting a founder effect. One of 200 control individuals was heterozygous for the mutation. The R565P substitution results from an 8839G-C transversion in exon 6 of the NAGLU gene.
Yogalingam et al. (2000) reported a patient with an attenuated form of Sanfilippo syndrome B (MPS3B; 252920) who was a compound heterozygote for 2 mutations in the NAGLU gene: an R297X substitution (609701.0003) and a phe48-to-leu (F48L) substitution. The F48L mutation was associated with a partially degraded polypeptide in a 16-hour chase experiment, suggesting that this missense mutation affects the processing and stability of NAGLU. It was associated with significant residual NAGLU activity sufficient to metabolize 34% of intracellular 35-S-labeled GAG storage, suggesting that some F48L-NAGLU was being correctly sorted to the lysosomal compartment. Yogalingam et al. (2000) suggested that the residual NAGLU activity could explain the attenuated phenotype in their patient.
In 2 sibs with an attenuated form of Sanfilippo syndrome B (MPS3B; 252920), Tanaka et al. (2002) identified compound heterozygosity for 2 mutations in the NAGLU gene: a phe314-to-leu (F314L) substitution and an R565P (609701.0009) substitution.
In a patient with a severe form of Sanfilippo syndrome B (MPS3B; 252920), Tanaka et al. (2002) identified homozygosity for an arg482-to-trp (R482W) mutation in the NAGLU gene.
In patients with mucopolysaccharidosis type IIIB (MPS3B; 252920), Beesley et al. (1998) identified a C-to-T transition in the NAGLU gene, resulting in an arg234-to-cys (R234C) substitution.
Mangas et al. (2008) identified the R234C mutation in 5 of 11 Portuguese patients with MPS3B. The mutation was the most common identified in this population, accounting for 32% of mutant alleles. Haplotype analysis showed that the R234C mutation arose on a founder haplotype common to both Spanish and Portuguese individuals. Mangas et al. (2008) postulated that the mutation had a single and relatively recent origin in the Iberian peninsula.
In 3 affected children in family 8600486 with severe intellectual disability, autism spectrum disorder, and coarse facial features, diagnosed as mucopolysaccharidosis type IIIB (MPS3B; 252920), Najmabadi et al. (2011) identified a homozygous G-to-A transition in the NAGLU gene at genomic coordinate chr17:37949244 (NCBI36), resulting in an arg565-to-gln (R565Q) substitution. Their parents, who were first cousins once removed, were carriers.
In affected members of a large French Canadian kindred with autosomal dominant axonal Charcot-Marie-Tooth disease type 2V (CMT2V; 616491), Tetreault et al. (2015) identified a heterozygous c.1208T-C transition (c.1208T-C, NM_000263.3) in exon 6 of the NAGLU gene, resulting in an ile403-to-thr (I403T) substitution at a highly conserved residue in the Tim-barrel domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP (build 137) or Exome Variant server databases, or in over 50 French Canadian controls. Patient leukocytes showed significantly decreased NAGLU enzyme activity (36-54% of controls), consistent with a detrimental effect of the mutation.
This variant is classified as a variant of unknown significance because its contribution to Charcot-Marie-Tooth disease has not been confirmed.
In 3 members of a North American family with autosomal dominant axonal Charcot-Marie-Tooth disease (see CMT2V, 616491), Tetreault et al. (2015) identified a heterozygous mutation in the NAGLU gene, resulting in a glu123-to-ter (E123X) substitution. The substitution was predicted to truncate the protein before the catalytic domain, thus eliminating the possibility of residual enzyme activity, but functional studies were not performed. In addition, at least 1 affected family member also carried a heterozygous missense mutation (V243M) in the CMT-associated GDAP1 gene (606598), which was of uncertain significance; functional studies of the GDAP1 variant were not performed. These patients had onset of mild muscle weakness and pain in their teens, followed by distal sensory impairment in mid-adulthood.
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