NAGA

protein-coding

alpha-N-acetylgalactosaminidase, the group of Galactosidases alpha

Gene summary

NAGA encodes the lysosomal enzyme alpha-N-acetylgalactosaminidase, which cleaves alpha-N-acetylgalactosaminyl moieties from glycoconjugates. Mutations in NAGA have been identified as the cause of Schindler disease types I and II (type II also known as Kanzaki disease). [provided by RefSeq, Jul 2008]

MANE transcript

NM_000262.3

Inheritance

ClinVar variants

P:67U:110B:126

Top phenotype

Kanzaki disease; Alpha-n-acetylgalactosaminidase deficiency; Schindler disease type I; Schindler disease type III

gnomAD constraint

pLI —, LoF o/e 0.88

Max pathogenic AF

—

Genomic locus

chr22:42,058,334-42,070,842

External References & Databases

Ensembl (ENSG00000198951)

Transcript & Mutation Effects

hg38 • Region Span ~12.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

alpha-N-acetylgalactosaminidase deficiency type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012222

Submitter: Orphanet

alpha-N-acetylgalactosaminidase deficiency type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012221

Submitter: Orphanet

alpha-N-acetylgalactosaminidase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0017779

Submitter: PanelApp Australia

alpha-N-acetylgalactosaminidase deficiency type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012221

Submitter: Labcorp Genetics (formerly Invitae)

alpha-N-acetylgalactosaminidase deficiency type 3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019264

Submitter: Orphanet

alpha-N-acetylgalactosaminidase deficiency type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012222

Submitter: G2P

alpha-N-acetylgalactosaminidase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017779

Submitter: ClinGen

The NAGA gene was first reported in relation to autosomal recessive alpha-N-acetylgalactosaminidase (NAGA) deficiency in 1990 (Wang et al., PMID: 2243144). NAGA is a lysosomal enzyme that hydrolyzes terminal D-galactosyl-N-acetamidodeoxy-alpha-D-galactosidic (alpha-GalNAc) residues from glycolipids and glycoproteins. Biallelic variants in NAGA have been reported in patients with various disorders including Schindler disease, type I (MIM# 609241; NAGA deficiency type I), Schindler disease, type III (MIM# 609241; NAGA deficiency type III), and Kanzaki disease (MIM# 609242; also known as Schindler disease, type II; NAGA deficiency type II). Of these conditions, Schindler disease, type I, has been reported as the most severe. This disorder was first described in two German brothers with infantile neuroaxonal dystrophy, with rapid and severe progression (Schindler et al, 1989, PubMed: 2733734). Schindler disease, type III, is less severe and can present with developmental, neurologic, and psychiatric manifestations in childhood. A different clinical presentation of NAGA deficiency, Kanzaki disease, was first reported in a Japanese patient and is characterized by angiokeratoma corporis diffusum and mild sensory neuropathy (Kanzaki et al, 1991, PubMed: 1907616). Of note, several sibling pairs have been reported with low NAGA activity, abnormal urine glycoproteins, and biallelic variants in NAGA, with one sibling presenting with severe clinical symptoms and an older sibling reported to asymptomatic, or having only mild symptoms. Furthermore, the severity of symptoms does not appear to correlate with the residual enzyme activity. Therefore, the clinical symptoms associated with NAGA deficiency are unclear and, presumably, additional factors have a role in the phenotypes reported in these patients (Keulemans et al, 1996, PMID: 8782044). For the purposes of this curation, reported cases have been lumped under the umbrella term, alpha-N-acetylgalactosaminidase deficiency (NAGA deficiency) (MONDO:0017779 ). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern in patients with NAGA deficiency. The biochemical phenotype (low NAGA activity and abnormal urine glycoproteins) appears to be consistent between patients even though the clinical symptoms in these patients is variable. NAGA deficiency is a rare condition. In this curation, data from 9 probands with 8 unique variants (7 missense, 1 nonsense) from 7 publications were collected (Wang et al, 1990, PMID: 2243144; Keulemans et al, 1996, PMID: 8782044; Wang et al, 1996, PMID: 8040340; Bakker et al, 2001, PMID: 11313741; Kodama et al, 2001, PMID: 11251574; Chabás et al, 2007, PMID: 17171432; Mohamed et al, 2020, PMID: 31468281) (Total 8.85 points for genetic evidence). The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence. This includes the biochemical function of NAGA, which is consistent with the biochemical findings in patients (Hermann et al, 1998, PMID: 9602128; Mohamed et al, 2020, PMID: 31468281), and a knock out mouse model with no evidence of neurological issues but widespread lysosomal storage of abnormal material in the nervous system and other organs, and focal axonal swellings or spheroids in the central nervous system (in “Schindler disease: deficient α-N-acetylgalactosaminidase activity", in Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Sixth Edition) Volume 1: 2020, Pages 589-598). In summary, NAGA is definitively associated with autosomal recessive NAGA deficiency. This classification was approved by the ClinGen Lysosomal Disorders Gene Curation Expert Panel on September 29, 2022 (SOP v9).

alpha-N-acetylgalactosaminidase deficiency type 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012222

Submitter: Genomics England PanelApp

alpha-N-acetylgalactosaminidase deficiency type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012221

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Kanzaki disease; Alpha-n-acetylgalactosaminidase deficiency; Schindler disease type I; Schindler disease type IIIAR

Manifestation: Biochemical; Dermatologic; 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

Refs: 2564952; 2243144; 7707696; 8071745; 8040340; 8782044; 11313741; 11251574; 14685826; 15619430

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NAGA variants in ClinVar

13 Conditions Cataloged

Alpha-N-acetylgalactosaminidase deficiency type 1Total: 317

Inborn genetic diseasesTotal: 54

Alpha-N-acetylgalactosaminidase deficiencyTotal: 43

not providedTotal: 39

Alpha-N-acetylgalactosaminidase deficiency type 2Total: 36

not specifiedTotal: 18

NAGA-related disorderTotal: 10

Intellectual disabilityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000262.3. 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			4 clinvar	121 clinvar		125
missense		5 clinvar	101 clinvar	4 clinvar	1 clinvar	111
nonsense	24 clinvar	6 clinvar	1 clinvar			31
start loss						0
frameshift	20 clinvar	1 clinvar	4 clinvar			25
splice donor/acceptor (+/-2bp)		11 clinvar				11
Total	44	23	110	125	1	303

Highest pathogenic variant AF is 0.0036490064

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000262.3	RefSeq	NP_000253.1	9	MANE Select
ENST00000396398.8	Ensembl	ENSP00000379680.3	9	MANE Select
NM_001362848.1	RefSeq	NP_001349777.1	9	Standard
NM_001362850.1	RefSeq	NP_001349779.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysosome - Homo sapiens (human)
Glycosphingolipid biosynthesis - globo and isoglobo series - Homo sapiens (human)
Glycosphingolipid biosynthesis - globoseries

Biological Process

oligosaccharide metabolic process
carbohydrate catabolic process
glycoside catabolic process
glycolipid catabolic process
glycosylceramide catabolic process

Molecular Function

alpha-galactosidase activity
alpha-N-acetylgalactosaminidase activity
protein homodimerization activity

Cellular Component

cytoplasm
lysosome
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396398
Coding exons: 9
Length: 12489
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 49
Defined: 125748
p: 0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.169	237	244	0.970	0.0000154	2723
Missense (PolyPhen)		70	76.964	0.90952		861
Synonymous	0.901	84	95.2	0.883	0.00000600	785
Loss of Function	0.510	18	20.5	0.878	0.00000100	210

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00020	0.00019	rare
South Asian	0.00046	0.00046	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides. Required for the breakdown of glycolipids. {ECO:0000269|PubMed:9741689}.;
Disease: DISEASE: Schindler disease (SCHIND) [MIM:609241]: Form of NAGA deficiency characterized by early-onset neuroaxonal dystrophy and neurological signs (convulsion during fever, epilepsy, psychomotor retardation and hypotonia). NAGA deficiency is typically classified in three main phenotypes: NAGA deficiency type I (Schindler disease or Schindler disease type I) with severe manifestations; NAGA deficiency type II (Kanzazi disease or Schindler disease type II) which is mild; NAGA deficiency type III (Schindler disease type III) characterized by mild-to-moderate neurologic manifestations. NAGA deficiency results in the increased urinary excretion of glycopeptides and oligosaccharides containing alpha-N-acetylgalactosaminyl moieties. Inheritance is autosomal recessive. {ECO:0000269|PubMed:2243144, ECO:0000269|PubMed:8782044}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Kanzaki disease (KANZD) [MIM:609242]: Autosomal recessive disorder characterized by late-onset, angiokeratoma corporis diffusum and mild intellectual impairment. {ECO:0000269|PubMed:11251574, ECO:0000269|PubMed:8040340}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.394

Intolerance Scores

LoFtool: 0.257
RVIS EVS: -0.31
RVIS percentile EVS: 32.06

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0945

Gene Damage Prediction

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