NAGLU

protein-coding

N-acetyl-alpha-glucosaminidase, the group of Glycoside hydrolases

Gene summary

This gene encodes an enzyme that degrades heparan sulfate by hydrolysis of terminal N-acetyl-D-glucosamine residues in N-acetyl-alpha-D-glucosaminides. Defects in this gene are the cause of mucopolysaccharidosis type IIIB (MPS-IIIB), also known as Sanfilippo syndrome B. This disease is characterized by the lysosomal accumulation and urinary excretion of heparan sulfate. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000263.4

Inheritance

AR, AD

ClinVar variants

P:353U:446B:488

Top phenotype

Mucopolysaccharidosis type IIIB (Sanfilippo syndrome B)

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr17:42,536,241-42,544,449

External References & Databases

Ensembl (ENSG00000108784)

Transcript & Mutation Effects

hg38 • Region Span ~8.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mucopolysaccharidosis type 3BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009656

Submitter: ClinGen

The relationship between the NAGLU gene and mucopolysaccharidosis type IIIB (MPS IIIB), an autosomal recessive lysosomal storage disorder, was evaluated using the ClinGen Clinical Validity Framework as of June 29, 2022. NAGLU encodes alpha-N-acetylglucosaminidase, a lysosomal enzyme that catalyzes the hydrolysis of terminal non-reducing N-acetyl-D-glucosamine residues in the degradation of heparan sulfate, a glycosaminoglycan (GAG) (PMID: 8650226). Among individuals with MPS IIIB, alpha-N-acetylglucosaminidase deficiency results in accumulation of incompletely degraded oligosaccharides in lysosomes in the brain and other tissues, resulting in neurodegeneration with variable extra-neurologic manifestations (as reviewed in PMID: 18392742, PMID: 11668611). The disease mechanism of MPS IIIB is loss of function. MPS IIIB was first reported in 1973 (Neufeld, Personal Communication. Bethesda, Md. 1973) and the first report of biallelic variants in NAGLU among patients with MPS IIIB was published in 1996 (PMID: 8650226). Both case-level (genetic) and experimental evidence support the relationship between MPS IIIB and NAGLU. Reported causal variants include missense, nonsense, frameshift, and splice-altering variants, as well as larger intragenic deletions (PMID: 11668611). In total, 10 variants from six probands in five publications were curated. Although there is additional published case-level evidence available, the maximum score for genetic evidence (12 points) has already been reached. Experimental evidence for the relationship between NAGLU and MPS IIIB includes the biochemical function of the gene product (the alpha-N-acetylglucosaminidase enzyme) being consistent with the clinical and biochemical findings identified individuals with MPS IIIB (PMID: 8650226, PMID:18392742, PMID:11668611), the biochemical and clinical features of a NAGLU knockout mouse animal (PMID: 10588735), and the impact of gene therapy among human MPS IIIB patients (PMID: 28713035). Additional experimental evidence is available, but the maximum score for experimental evidence (6 points) has already been reached. In sum, NAGLU is definitively associated with MPS IIIB. The association has been repeatedly demonstrated in both clinical and research settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Lysosomal Diseases GCEP on August 2, 2022 (SOP v9).

mucopolysaccharidosis type 3BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009656

Submitter: Natera

mucopolysaccharidosis type 3BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009656

Submitter: Genomics England PanelApp

mucopolysaccharidosis type 3BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009656

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease axonal type 2VSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014665

Submitter: PanelApp Australia

mucopolysaccharidosis type 3BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009656

Submitter: G2P

Charcot-Marie-Tooth disease axonal type 2VLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014665

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease axonal type 2VSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014665

Submitter: Orphanet

mucopolysaccharidosis type 3BSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009656

Submitter: Orphanet

mucopolysaccharidosis type 3BDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009656

Submitter: Myriad Women's Health

mucopolysaccharidosis type 3BSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009656

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mucopolysaccharidosis type IIIB (Sanfilippo syndrome B)AR

Manifestation: Biochemical; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: BMT has been reported as beneficial

Refs: 4261742; 3118713; 1606713; 1293388; 8650226; 3118713; 11068184; 12202988; 15933803; 18218046; 20852935; 21937992; 21712855; 22976768; 25818867

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NAGLU variants in ClinVar

25 Conditions Cataloged

Mucopolysaccharidosis, MPS-III-BTotal: 1343

Charcot-Marie-Tooth disease axonal type 2VTotal: 1182

not providedTotal: 183

not specifiedTotal: 121

Inborn genetic diseasesTotal: 79

NAGLU-related disorderTotal: 77

MucopolysaccharidosisTotal: 8

Intellectual disabilityTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000263.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			14 clinvar	465 clinvar		479
missense	18 clinvar	119 clinvar	422 clinvar	21 clinvar	2 clinvar	582
nonsense	35 clinvar	27 clinvar	4 clinvar			66
start loss	3 clinvar	3 clinvar				6
frameshift	77 clinvar	53 clinvar	4 clinvar			134
splice donor/acceptor (+/-2bp)	7 clinvar	11 clinvar	2 clinvar			20
Total	140	213	446	486	2	1287

Highest pathogenic variant AF is 0.00014993253

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000263.4	RefSeq	NP_000254.2	6	MANE Select
ENST00000225927.7	Ensembl	ENSP00000225927.1	6	MANE Select
ENST00000586516.5	Ensembl	ENSP00000467135.1	4	Standard
ENST00000590358.1	Ensembl	ENSP00000466892.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Glycosaminoglycan degradation - Homo sapiens (human)
Metabolism of carbohydrates
HS-GAG degradation
Heparan sulfate/heparin (HS-GAG) metabolism

Biological Process

glycosaminoglycan catabolic process
lysosome organization
nervous system development
cerebellar Purkinje cell layer development
middle ear morphogenesis

Molecular Function

alpha-N-acetylglucosaminidase activity

Cellular Component

lysosome
lysosomal lumen
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000225927
Coding exons: 6
Length: 8278
Individuals with no LoFs: 125687
Homozygous LoFs: 0
Heterozygous LoFs: 61
Defined: 125748
p: 0.000243

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.988	313	366	0.855	0.0000239	4692
Missense (PolyPhen)		119	152.07	0.78253		1907
Synonymous	-0.513	168	160	1.05	0.0000108	1591
Loss of Function	1.96	17	28.2	0.602	0.00000180	262

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00040	0.00037	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00031	0.00030	rare
South Asian	0.00023	0.00023	rare
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the degradation of heparan sulfate.;
Disease: DISEASE: Charcot-Marie-Tooth disease 2V (CMT2V) [MIM:616491]: An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2V is an autosomal dominant sensory neuropathy with late onset. The main clinical feature is recurrent leg pain that progresses to constant painful paraesthesias in the feet and later the hands. As it evolves, some patients develop a mild sensory ataxia. {ECO:0000269|PubMed:25818867}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.528

Intolerance Scores

LoFtool: 0.159
RVIS EVS: -0.75
RVIS percentile EVS: 13.67

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.731

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium