ASPA

Summary

ASPA (aspartoacylase, HGNC:756) is a protein-coding gene on chromosome 17p13.2, encoding Aspartoacylase (P45381). Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate.

This gene encodes an enzyme that catalyzes the conversion of N-acetyl_L-aspartic acid (NAA) to aspartate and acetate. NAA is abundant in the brain where hydrolysis by aspartoacylase is thought to help maintain white matter. This protein is an NAA scavenger in other tissues. Mutations in this gene cause Canavan disease. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 443 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Canavan disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 536 total — 63 pathogenic, 92 likely-pathogenic (top 6% of genes corpus-wide)
• GTEx eGene: eQTL in 39 tissues, sQTL in 3 (q < 0.05)
• Phenotypes (HPO): 61
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.10 (unconstrained)
• MANE Select transcript: NM_000049

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:756
Approved symbol	ASPA
Name	aspartoacylase
Location	17p13.2
Locus type	gene with protein product
Status	Approved
Aliases	ASP, ACY2
Ensembl gene	ENSG00000108381
Ensembl biotype	protein_coding
OMIM	608034
Entrez	443

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 3 nonsense_mediated_decay

MANE Select: ENST00000263080

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 5: 2

ENST00000263080, ENST00000456349, ENST00000571278, ENST00000577034, ENST00000858436, ENST00001096853, ENST00001121324, ENST00001121325, ENST00001121326, ENST00001127118, ENST00001127119, ENST00001138468

RefSeq mRNA: 2 — MANE Select: NM_000049 NM_000049, NM_001128085

CCDS: CCDS11028

Canonical transcript exons

ENST00000263080 — 6 exons

Exon	Start	End
ENSE00000669166	3489235	3489342
ENSE00000669168	3494350	3494459
ENSE00001116147	3475997	3476395
ENSE00001923034	3498891	3503405
ENSE00003474668	3483499	3483592
ENSE00003477626	3481603	3481798

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 97.25.

FANTOM5 (CAGE): breadth broad, TPM avg 3.5357 / max 271.3708, expressed in 322 samples.

Highest expression (Bgee): corpus callosum, nephron tubule, medial globus pallidus, globus pallidus, kidney epithelium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ASPA is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 39 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 42 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	9.5e-38	-0.59	17:3531768:A:G
Heart Left Ventricle	eqtl	1.3e-18	-0.41	17:3476521:T:C
Heart Atrial Appendage	eqtl	2.2e-16	-0.30	17:3476521:T:C
Adrenal Gland	eqtl	1.6e-15	-0.47	17:3513015:A:C
Artery Tibial	eqtl	2.3e-15	-0.28	17:3530249:A:G
Skin Not Sun Exposed Suprapubic	eqtl	1.4e-10	-0.30	17:3530821:C:T
Brain Cerebellum	eqtl	2.1e-10	-0.51	17:3534518:G:C
Thyroid	eqtl	3.3e-10	-0.21	17:3530301:C:T
Artery Aorta	eqtl	1.0e-09	-0.30	17:3483264:T:C
Nerve Tibial	sqtl	1.2e-09	-0.46	17:3492694:A:G
Adipose Visceral Omentum	eqtl	7.3e-09	-0.22	17:3530249:A:G
Brain Spinal cord cervical c-1	eqtl	1.2e-07	-0.70	17:3531445:C:CCAGGA
Brain Cerebellar Hemisphere	eqtl	2.6e-07	-0.43	17:3534518:G:C
Esophagus Muscularis	eqtl	6.2e-07	-0.31	17:3527865:C:G
Stomach	eqtl	6.6e-07	-0.30	17:3530301:C:T
Pituitary	eqtl	7.9e-07	-0.24	17:3475582:C:T
Pancreas	eqtl	9.4e-07	+0.28	17:3512878:A:G
Skin Sun Exposed Lower leg	eqtl	5.1e-06	-0.22	17:3541658:A:C
Brain Hypothalamus	eqtl	6.6e-06	-0.37	17:3531768:A:G
Brain Hippocampus	eqtl	4.3e-05	-0.27	17:3531445:C:CCAGGA

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
158870	3.1923	306
158869	0.1427	68
158871	0.0949	45
158874	0.0569	35
158873	0.0259	14
158872	0.0230	12

Top tissues by expression

showing 100 of 293 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	97.25	gold quality
nephron tubule	UBERON:0001231	95.27	gold quality
medial globus pallidus	UBERON:0002477	92.90	gold quality
globus pallidus	UBERON:0001875	92.56	gold quality
kidney epithelium	UBERON:0004819	92.20	gold quality
jejunal mucosa	UBERON:0000399	92.14	gold quality
trigeminal ganglion	UBERON:0001675	92.12	gold quality
inferior vagus X ganglion	UBERON:0005363	90.97	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.61	gold quality
endothelial cell	CL:0000115	90.47	gold quality
spinal cord	UBERON:0002240	89.85	gold quality
inferior olivary complex	UBERON:0002127	89.81	gold quality
renal glomerulus	UBERON:0000074	89.66	gold quality
substantia nigra	UBERON:0002038	89.36	gold quality
postcentral gyrus	UBERON:0002581	89.12	gold quality
metanephric glomerulus	UBERON:0004736	88.94	gold quality
midbrain	UBERON:0001891	88.77	gold quality
lateral globus pallidus	UBERON:0002476	88.67	gold quality
dorsal root ganglion	UBERON:0000044	88.64	gold quality
subthalamic nucleus	UBERON:0001906	88.45	gold quality
Brodmann (1909) area 46	UBERON:0006483	87.94	gold quality
Ammon’s horn	UBERON:0001954	87.80	gold quality
parietal lobe	UBERON:0001872	87.44	gold quality
adult organism	UBERON:0007023	87.29	gold quality
substantia nigra pars reticulata	UBERON:0001966	86.65	gold quality
tibial nerve	UBERON:0001323	86.33	gold quality
kidney	UBERON:0002113	86.03	gold quality
adult mammalian kidney	UBERON:0000082	85.92	gold quality
cranial nerve II	UBERON:0000941	85.48	gold quality
medulla oblongata	UBERON:0001896	85.38	gold quality
putamen	UBERON:0001874	85.27	gold quality
cortex of kidney	UBERON:0001225	85.15	gold quality
amygdala	UBERON:0001876	84.89	gold quality
pons	UBERON:0000988	84.80	gold quality
duodenum	UBERON:0002114	84.47	gold quality
dorsal plus ventral thalamus	UBERON:0001897	84.14	gold quality
jejunum	UBERON:0002115	84.02	gold quality
parietal pleura	UBERON:0002400	83.54	gold quality
CA1 field of hippocampus	UBERON:0003881	83.48	gold quality
temporal lobe	UBERON:0001871	83.12	gold quality
hypothalamus	UBERON:0001898	82.97	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	82.57	gold quality
substantia nigra pars compacta	UBERON:0001965	82.49	gold quality
sperm	CL:0000019	82.41	silver quality
caudate nucleus	UBERON:0001873	82.36	gold quality
ventral tegmental area	UBERON:0002691	82.25	gold quality
superior vestibular nucleus	UBERON:0007227	82.02	gold quality
entorhinal cortex	UBERON:0002728	81.88	gold quality
superior frontal gyrus	UBERON:0002661	81.31	gold quality
middle frontal gyrus	UBERON:0002702	80.95	gold quality
prefrontal cortex	UBERON:0000451	80.66	gold quality
metanephros	UBERON:0000081	80.58	gold quality
telencephalon	UBERON:0001893	80.53	gold quality
sural nerve	UBERON:0015488	80.20	gold quality
adipose tissue	UBERON:0001013	79.83	gold quality
pleura	UBERON:0000977	79.72	gold quality
male germ cell	CL:0000015	79.70	silver quality
hindlimb stylopod muscle	UBERON:0004252	79.61	gold quality
Brodmann (1909) area 9	UBERON:0013540	79.59	gold quality
nucleus accumbens	UBERON:0001882	78.97	gold quality
cerebral cortex	UBERON:0000956	78.95	gold quality
frontal cortex	UBERON:0001870	78.93	gold quality
biceps brachii	UBERON:0001507	78.78	gold quality
adipose tissue of abdominal region	UBERON:0007808	78.68	gold quality
connective tissue	UBERON:0002384	78.65	gold quality
occipital lobe	UBERON:0002021	78.64	gold quality
renal medulla	UBERON:0000362	78.42	gold quality
primary visual cortex	UBERON:0002436	78.28	gold quality
forebrain	UBERON:0001890	78.24	gold quality
right frontal lobe	UBERON:0002810	78.09	gold quality
vastus lateralis	UBERON:0001379	78.05	silver quality
omental fat pad	UBERON:0010414	77.97	gold quality
peritoneum	UBERON:0002358	77.92	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	77.92	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	77.84	gold quality
central nervous system	UBERON:0001017	77.82	gold quality
olfactory bulb	UBERON:0002264	77.74	gold quality
upper leg skin	UBERON:0004262	77.62	gold quality
brain	UBERON:0000955	77.43	gold quality
neocortex	UBERON:0001950	77.32	gold quality
Brodmann (1909) area 10	UBERON:0013541	76.93	gold quality
skin of hip	UBERON:0001554	76.84	gold quality
quadriceps femoris	UBERON:0001377	76.81	silver quality
metanephros cortex	UBERON:0010533	76.46	gold quality
orbitofrontal cortex	UBERON:0004167	76.30	gold quality
rectum	UBERON:0001052	76.24	gold quality
colonic epithelium	UBERON:0000397	76.17	gold quality
epithelial cell of pancreas	CL:0000083	76.13	silver quality
small intestine	UBERON:0002108	76.03	gold quality
seminal vesicle	UBERON:0000998	75.92	gold quality
subcutaneous adipose tissue	UBERON:0002190	75.90	gold quality
cingulate cortex	UBERON:0003027	75.76	gold quality
urinary bladder	UBERON:0001255	75.64	gold quality
muscle organ	UBERON:0001630	75.62	gold quality
anterior cingulate cortex	UBERON:0009835	75.62	gold quality
skeletal muscle organ	UBERON:0014892	75.62	gold quality
muscle of leg	UBERON:0001383	75.36	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	75.09	gold quality
tibia	UBERON:0000979	74.94	gold quality
left uterine tube	UBERON:0001303	74.81	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.23
E-MTAB-6379	no	76.50
E-MTAB-9543	no	1.22

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Corpus callosum	tissue	106.9
Spinal cord	tissue	48.8
Medulla oblongata	tissue	48.4
Midbrain	tissue	48.1
Substantia nigra	tissue	45.6
Caudate putamen	tissue	40.4
Periaqueductal gray	tissue	38.9
Nucleus accumbens	tissue	38.1
Superior colliculi	tissue	37.1
Thalamus	tissue	35.7
Kidney	tissue	35.6	high
Putamen	tissue	35.5
Pons	tissue	34.5
Ventral forebrain	tissue	30.7
Hippocampus	tissue	29.9	medium
Hypothalamus	tissue	27.2
Hippocampal formation	tissue	26.4
Postcentral gyrus	tissue	24.9
Locus coeruleus	tissue	24.3
Septum	tissue	23.7
Amygdala	tissue	20.4
Cerebral cortex	tissue	19.6	high
Retrosplenial cortex	tissue	19.6
Frontal cortex	tissue	18.7
Occipital cortex	tissue	17.6
Choroid plexus	tissue	17.1
Somatosensory cortex	tissue	15.8
Insular cortex	tissue	15.3
Motor cortex	tissue	15.2
Olfactory bulb	tissue	15.2
Small intestine	tissue	14.7	low
Retrosplenial and cingulate cortex	tissue	14.7
Prefrontal cortex	tissue	14.6
Basal ganglia	tissue	14.6	medium
Cerebellum	tissue	14.4	high
Tongue	tissue	14.0
Liver	tissue	14.0	low
Temporal cortex	tissue	13.2
Adipose tissue	tissue	13.0	not detected
Entorhinal cortex	tissue	12.8
Skeletal muscle	tissue	11.1	low
Duodenum	tissue	10.6	low
Testis	tissue	6.2	medium
Cervix	tissue	5.9	not detected
Urinary bladder	tissue	5.8	low
Epididymis	tissue	5.5	not detected
Spleen	tissue	5.1	not detected
Skin 1	tissue	4.9	not detected
Fallopian tube	tissue	4.9	not detected
Seminal vesicle	tissue	4.7	not detected
Esophagus	tissue	4.6	not detected
Rectum	tissue	4.6	low
Endometrium 1	tissue	4.2	not detected
Stomach 1	tissue	4.1	low
Adrenal gland	tissue	4.1	low
Vagina	tissue	4.0	not detected
Colon	tissue	3.8	low
Prostate	tissue	3.8	not detected
Gallbladder	tissue	3.4	not detected
Breast	tissue	3.3	not detected

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Parieto-temporal junction (white matter) (125.1), Temporal white matter (119.3), Corpus callosum, genu (white matter) (113.1), Area striata (white matter) (112.2), White matter (106.9).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ASPA by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

23 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-6516-3P	99.65	68.57	1238
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-96-3P	97.47	68.03	839
HSA-MIR-3139	96.68	66.77	652
HSA-MIR-28-5P	96.16	66.12	579
HSA-MIR-708-5P	96.16	66.12	576
HSA-MIR-675-3P	95.77	69.27	675

Functional genomics

gnomAD constraint: pLI 4.28e-05, LOEUF 1.1, missense Z 1.25 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000263080 — one region, missense o/e 0.86. ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• the ASPA gene was analysed in 22 unrelated non-Jewish patients with Canavan disease, and 24 different mutations were found (PMID:12638939)
• Mild-onset presentation of Canavan’s disease associated with novel G212A point mutation in aspartoacylase gene (PMID:16437572)
• molecular weight of the purified enzyme is higher than predicted, suggesting the presence of post-translational modifications. Deglycosylation of aspartoacylase or mutation at glycosylation site causes decreased enzyme stability and catalytic activity (PMID:16669630)
• a green fluorescent protein-human ASPA fusion protein larger than the permissible size for the nuclear pore complex was enzymatically active and showed mixed nuclear-cytoplasmic distribution. (PMID:16935940)
• The finding that wild-type and Glu178Asp have the same K(m) but different k(cat) values confirms the idea that the carboxylate group contributes importantly to the enzymatic activity of aspartoacylase. (PMID:17027983)
• the N-terminal domain of aspartoacylase adopts a protein fold similar to that of zinc-dependent hydrolases related to carboxypeptidases A (PMID:17194761)
• These results show that aspartoacylase is a member of the caboxypeptidase A family and offer novel explanations for most loss-of-function aspartoacylase mutations associated with Canavan Disease. (PMID:17391648)
• New structure of human aspartoacylase complexed with a catalytic intermediate analogue, N-phosphonomethyl- l-aspartate, supports a carboxypeptidase-type mechanism for hydrolysis of the amide bond of the substrate, N-acetyl- l-aspartate. (PMID:18293939)
• We report on an Italian female patient with Canavan disease due to a missense mutation of the aspartoacylase gene and a 17p13.3 chromosomal microdeletion (PMID:22019069)
• Gene ASPA (NM_000049) was undertaken to sequence for mutation analysis. (PMID:22219087)
• a novel mutation Y88X within the aspartoacylase gene in a consanguineous family with an affected child diagnosed as Canavan disease. (PMID:22468686)
• Human aspartoacylase gene expression was high not only in brain and kidney, but also in lung and liver. (PMID:22750302)
• This is the first case report of ASPA mutation studies in Canavan disease from Indian subcontinent. (PMID:22878930)
• report of 2 Egyptian sibling patients suspected of Canavan disease (CD); study revealed homozygosity for substitution T530C (Ile177Thr) in exon 4 of the ASPA gene in both sibs; substitution T530C (Ile177Thr) results in a novel missense mutation causing a CD phenotype with severe clinical characteristics (PMID:24036223)
• Definitive evidence is presented to show that the recombinantly-expressed human aspartoacylase is not a glycoprotein. (PMID:24632142)
• Four ASPA missense mutations associated with Canavan disease are structurally characterized. (PMID:25003821)
• Allosteric Control of N-Acetyl-Aspartate Hydrolysis by the Y231C and F295S Mutants of Human Aspartoacylase (PMID:30431265)
• In one case, the homozygous pathogenic variant NM_000049.2:c.914C>A;p.Ala305Glu, which is previously reported in ClinVar, in the gene ASPA was identified causing Canavan disease. In the second case, the homozygous novel variant NM_000487.5:c.256C>G;p.Arg86Gly in the gene ARSA was identified causing metachromatic leukodystrophy. (PMID:30834272)
• Mapping the degradation pathway of a disease-linked aspartoacylase variant. (PMID:33914734)
• Aspartoacylase promotes the process of tumour development and is associated with immune infiltrates in gastric cancer. (PMID:37391709)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	aspa	ENSDARG00000005154
mus_musculus	Aspa	ENSMUSG00000020774
rattus_norvegicus	Aspa	ENSRNOG00000019659

Paralogs (1): ACY3 (ENSG00000132744)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:87914) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 62 distinct phenotype terms.

Mouse phenotype (MP)	Records
tremors	5
decreased locomotor activity	5
impaired coordination	5
spongiform encephalopathy	5
decreased body weight	4
ataxia	4
abnormal gait	4
brain vacuoles	4
decreased body size	3
megacephaly	2
hyperactivity	2
decreased startle reflex	2
seizures	2
premature death	2
abnormal brain morphology	2
decreased vertical activity	2
astrocytosis	2
lethargy	2
axon degeneration	2
decreased bone mineral density	1
muscle weakness	1
paralysis	1
abnormal diencephalon morphology	1
abnormal myelination	1
demyelination	1

+37 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Prochlorococcus marinus str. NATL1A	A2C055	99.3%	Diamond
Prochlorococcus marinus str. NATL2A	Q46HE9	99.3%	Diamond
Pongo abelii	Q5R9E0	99.0%	Diamond
Macaca fascicularis	Q60HH2	97.8%	Diamond
Sus scrofa	B1PK17	95.2%	Diamond
Bos taurus	P46446	95.2%	Diamond
Trichormus variabilis ATCC 29413	Q3MC79	94.8%	Diamond
Nostoc sp. PCC 7120 = FACHB-418	Q8YQC1	94.8%	Diamond
Prochlorococcus marinus str. AS9601	A2BP19	91.4%	Diamond
Prochlorococcus marinus str. MIT 9215	A8G2N0	91.4%	Diamond
Xenopus laevis	A0JMS7	90.4%	Diamond
Xenopus tropicalis	Q5BJ91	90.4%	Diamond
Prochlorococcus marinus str. MIT 9301	A3PAU1	90.0%	Diamond
Prochlorococcus marinus str. MIT 9312	Q31CV9	87.7%	Diamond
Prochlorococcus marinus str. MIT 9515	A2BUK0	79.9%	Diamond
Prochlorococcus marinus subsp. pastoris str. CCMP1986	P59830	79.9%	Diamond
Synechococcus sp. CC9605	Q3AM91	64.0%	Diamond
Synechococcus sp. CC9902	Q3AV13	64.0%	Diamond
Parasynechococcus marenigrum WH 8102	P59829	63.2%	Diamond
Prochlorococcus marinus str. MIT 9313	Q7V5L6	58.1%	Diamond
Prochlorococcus marinus subsp. marinus str. CCMP1375	P72208	56.2%	Diamond
Acaryochloris marina MBIC11017	B0C2K7	55.9%	Diamond
Trichodesmium erythraeum IMS101	Q10VR3	55.9%	Diamond
Synechocystis sp. PCC 6803 substr. Kazusa	P73211	42.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
CTNS	protein-coding	1497
TRPV3	protein-coding	162514
SHPK	protein-coding	23729
TRPV1	protein-coding	7442
SPATA22	protein-coding	84690
OR1E2	protein-coding	8388
OR3A3	protein-coding	8392
P2RX5-TAX1BP3	ncRNA	100533970
TAX1BP3	protein-coding	30851
OR1E1	protein-coding	8387
OR3A2	protein-coding	4995
OR1R1	protein-coding	9596

Protein

Protein identifiers

Aspartoacylase — P45381 (reviewed: P45381)

Alternative names: Aminoacylase-2

All UniProt accessions (4): P45381, I3L0T3, I3L4M0, Q6FH48

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate. NAA occurs in high concentration in brain and its hydrolysis NAA plays a significant part in the maintenance of intact white matter. In other tissues it acts as a scavenger of NAA from body fluids.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Brain white matter, skeletal muscle, kidney, adrenal glands, lung and liver.

Disease relevance. Canavan disease (CAND) [MIM:271900] A rare neurodegenerative condition of infancy or childhood characterized by white matter vacuolization and demyelination that gives rise to a spongy appearance. The clinical features are onset in early infancy, atonia of neck muscles, hypotonia, hyperextension of legs and flexion of arms, blindness, severe mental defect, megalocephaly, and death by 18 months on the average. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the AspA/AstE family. Aspartoacylase subfamily.

RefSeq proteins (2): NP_000040, NP_001121557 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007036	Aste_AspA_hybrid_dom	Domain
IPR016708	Aspartoacylase	Family
IPR050178	AspA/AstE_fam	Family
IPR055438	AstE_AspA_cat	Domain

Pfam: PF04952, PF24827

Enzyme classification (BRENDA)

• EC 3.5.1.15 — aspartoacylase (BRENDA: 16 organisms, 65 substrates, 14 inhibitors, 22 Km, 13 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N-ACETYLASPARTIC ACID	0.12–0.36	4
N-ACETYLASPARTATE	0.163–1.69	2
N-ACYL L-ASPARTIC ACID	0.2	2
N-ACYL-L-ASPARTIC ACID	0.85–5.1	2
N-TRIFLUOROACETYLASPARTIC ACID	0.15–0.21	2
N-ACETYL-L-ASPARTATE	0.36	1
N-ACETYL-L-ASPARTIC ACID	0.1	1
N-CHLOROACETYL-L-ASPARTATE	0.59	1
N-DICHLOROACETYL-L-ASPARTATE	0.23	1
N-FORMYL-L-ASPARTATE	0.95	1
N-TRIFLUOROACETYL-L-ASPARTATE	0.21	1

Catalyzed reactions (Rhea)

• an N-acyl-L-aspartate + H2O = a carboxylate + L-aspartate (RHEA:10872)
• N-acetyl-L-aspartate + H2O = L-aspartate + acetate (RHEA:59408)

UniProt features (96 total): sequence variant 44, strand 19, helix 11, binding site 9, mutagenesis site 8, turn 2, chain 1, active site 1, site 1

Structure

Experimental structures (PDB)

8 structures by resolution:

PDB	Title	Method	Resolution (Å)
4MXU	Human brain aspartoacylase mutant K213E complex with intermediate analog …	X-RAY DIFFRACTION	2.6
2O4H	Human brain aspartoacylase complex with intermediate analog …	X-RAY DIFFRACTION	2.7
2O53	Crystal structure of apo-Aspartoacylase from human brain	X-RAY DIFFRACTION	2.7
2I3C	Crystal Structure of an Aspartoacylase from Homo Sapiens	X-RAY DIFFRACTION	2.8
2Q51	Ensemble refinement of the protein crystal structure of an aspartoacylase from Homo …	X-RAY DIFFRACTION	2.8
4MRI	Human brain aspartoacylase mutant F295S complex with intermediate analog …	X-RAY DIFFRACTION	2.8
4TNU	Human brain aspartoacylase mutant Y231C complex with intermediate analog …	X-RAY DIFFRACTION	2.9
4NFR	Human brain aspartoacylase mutant E285A complex with intermediate analog …	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P45381-F1	96.14	0.94

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Metabolic proteins, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital disorders of metabolism, Congenital disorders of amino acid metabolism

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH enhanced · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2)

Position	Role
178	proton donor/acceptor
63	transition state stabilizer

Ligand- & substrate-binding residues (9)

Position	Role
288	N-acetyl-L-aspartate
21	Zn(2+)
24	Zn(2+)
63	N-acetyl-L-aspartate
70	N-acetyl-L-aspartate
71	N-acetyl-L-aspartate
116	Zn(2+)
164	N-acetyl-L-aspartate
168	N-acetyl-L-aspartate

Mutagenesis-validated functional residues (8)

Position	Phenotype
71	reduces activity by 99%.
164	reduces activity by 99%.
168	reduces activity by 99%.
178	reduces activity by 99%.
178	abolishes enzymatic activity.
285	5-fold decrease in activity.
288	reduces activity by 99%.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-8963693	Aspartate and asparagine metabolism	curated
R-HSA-1430728	Metabolism	—
R-HSA-71291	Metabolism of amino acids and derivatives	—

MSigDB gene sets: 257 (showing top): JAEGER_METASTASIS_DN, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, HNF1_Q6, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, SRF_Q5_01, CAIRO_HEPATOBLASTOMA_CLASSES_DN, SRF_C, KEGG_HISTIDINE_METABOLISM, TGCTGAY_UNKNOWN, IRF1_Q6, HFH8_01, WTGAAAT_UNKNOWN

GO Biological Process (2): acetate metabolic process (GO:0006083), aspartate metabolic process (GO:0006531)

GO Molecular Function (7): hydrolase activity, acting on ester bonds (GO:0016788), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides (GO:0016811), aspartoacylase activity (GO:0019807), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): nucleus (GO:0005634), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

14 GO namespaces:

Category	Terms
cellular anatomical structure	2
monocarboxylic acid metabolic process	1
amino acid metabolic process	1
dicarboxylic acid metabolic process	1
hydrolase activity	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
protein binding	1
cation binding	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intracellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 12 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
cytosol	CC	direct assay
aspartoacylase activity	MF	direct assay
identical protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 578 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASPA	ACY1	Q03154	965
ASPA	ASPNAT	Q8N9F0	782
ASPA	APEH	P13798	674
ASPA	CNP	P09543	594
ASPA	ARSA	P15289	491
ASPA	MBP	P02686	483
ASPA	MAL	P21145	469
ASPA	SHPK	Q9UHJ6	465
ASPA	SUMF1	Q8NBK3	463
ASPA	SPATA22	Q8NHS9	444
ASPA	EIF2B2	P49770	435
ASPA	OLIG2	Q13516	423
ASPA	SPHK1	Q9NYA1	386
ASPA	CPA6	Q8N4T0	363
ASPA	TAF6	P49848	360

IntAct

Human interaction partners of ASPA in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

10 partners by confidence:

Partner	Interaction type	MIscore	Records
ACY3	physical association	0.810	15
KEAP1	physical association	0.600	4
COPS3	physical association	0.560	3
DUSP29	physical association	0.560	3
PIAS1	physical association	0.560	3
UBQLN2	physical association	0.560	3
UBQLN3	physical association	0.560	3
UBQLNL	physical association	0.560	3
PGK2	association	0.350	1
HUNK	physical association	0.000	1

BioGRID (10 interactions; top human partners by supporting records): ACY3 (Two-hybrid; 3 records), DUPD1 (Two-hybrid), HUNK (Two-hybrid), PGK2 (Affinity Capture-MS), PRNP (Affinity Capture-MS), RUFY1 (Affinity Capture-MS), WASL (Affinity Capture-MS)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
ASPA	“down-regulates quantity”	N-acetyl-L-aspartate(2-)	“chemical modification”
ASPA	“up-regulates quantity”	“acetic acid”	“chemical modification”
ASPA	“up-regulates quantity”	L-aspartate(1-)	“chemical modification”

Disease & clinical

Genetic variants

Variant evidence for ASPA: 536 ClinVar records (155 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

536 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	63
Likely pathogenic	92
Uncertain significance	140
Likely benign	169
Benign	13

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 155 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
2607	NM_000049.4(ASPA):c.914C>A (p.Ala305Glu)	Pathogenic	criteria provided, multiple submitters, no conflicts	20
2609	NM_000049.4(ASPA):c.693C>A (p.Tyr231Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	18
370554	NM_000049.4(ASPA):c.244dup (p.Met82fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	10
2608	NM_000049.4(ASPA):c.654C>A (p.Cys218Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
188803	NM_000049.4(ASPA):c.859G>A (p.Ala287Thr)	Pathogenic	criteria provided, multiple submitters, no conflicts	8
188940	NM_000049.4(ASPA):c.541C>A (p.Pro181Thr)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
189005	NM_000049.4(ASPA):c.244_245del (p.Met82fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
662022	NM_000049.4(ASPA):c.550C>T (p.Gln184Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
551932	NM_000049.4(ASPA):c.382del (p.Glu129fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
2678898	NM_000049.4(ASPA):c.34_46del (p.Gln12fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2854616	NM_000049.4(ASPA):c.10delinsGG (p.Cys4fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
554476	NM_000049.4(ASPA):c.539G>T (p.Gly180Val)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	6
550715	NM_000049.4(ASPA):c.527-2A>C	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5
556181	NM_000049.4(ASPA):c.89T>C (p.Leu30Pro)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5
950717	NM_000049.4(ASPA):c.941A>G (p.Ter314Trp)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	5

Per-variant reference — Sugi Variant

Explore ASPA’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 388):

Position(s)	Effect	Δscore	Sites
17:3489343–3489344	donor_loss	1.0000	5
17:3481345	acceptor_gain	0.9900
17:3481356	acceptor_gain	0.9900
17:3481591	acceptor_gain	0.9900
17:3483593–3483594	donor_loss	0.9900	6
17:3489233–3489234	acceptor_loss	0.9900	6
17:3494460–3494461	donor_loss	0.9900	6
17:3481763	donor_gain	0.9800
17:3483497–3483498	acceptor_loss	0.9800	6
17:3483597	donor_loss	0.9800

AlphaMissense

598 missense substitutions predicted likely pathogenic (of 2,087 scored), across 170 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H116	8	0.979	0.994
D114	8	0.977	0.989
H21	8	0.975	0.989
F282	8	0.970	0.996
D68	8	0.965	0.985
N70	8	0.953	0.989
D251	8	0.945	0.987
F73	8	0.922	0.991
F295	8	0.806	0.934
E285	7	0.986	0.996
E24	7	0.982	0.996
E178	7	0.974	0.992
W252	7	0.960	0.993
E89	7	0.949	0.977
F262	7	0.943	0.979
N284	7	0.936	0.987
N54	7	0.931	0.992
F205	7	0.871	0.971
M122	7	0.825	0.901
M195	7	0.785	0.871

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Kidney Renal Clear Cell Carcinoma)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Papillary Cell Carcinoma (TCGA)	favorable	3.01e-06
Breast Invasive Carcinoma (validation)	favorable	0.000474
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000507

Disease associations

OMIM: gene MIM:608034 | disease phenotypes: MIM:271900, MIM:219750, MIM:219900, MIM:125853, MIM:209850

GenCC curated gene-disease

3 curated gene-disease records:

Disease	Classification	Inheritance	Records
Canavan disease	Definitive	Autosomal recessive	5
severe Canavan disease	Supportive	Autosomal recessive
mild Canavan disease	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
Canavan disease	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (12 panels, 12 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

12 panels:

Panel	Rating
DDG2P	green
Early onset or syndromic epilepsy	green
Fetal anomalies	green
Hypotonic infant	green
Inherited white matter disorders	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Likely inborn error of metabolism	green
Paediatric disorders	green
Undiagnosed metabolic disorders	green
Unexplained death in infancy and sudden unexplained death in childhood	green
White matter disorders and cerebral calcification - childhood onset	green

Mondo (7): Canavan disease (MONDO:0010079), ocular cystinosis (MONDO:0009064), juvenile nephropathic cystinosis (MONDO:0009066), mild Canavan disease (MONDO:0017831), type 2 diabetes mellitus (MONDO:0005148), autism (MONDO:0005260), severe Canavan disease (MONDO:0017830)

Orphanet (5): Canavan disease (Orphanet:141), Cystinosis (Orphanet:213), Juvenile nephropathic cystinosis (Orphanet:411634), Ocular cystinosis (Orphanet:411641), Mild Canavan disease (Orphanet:314918)

HPO phenotypes

showing 60 of 61 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000365	Hearing impairment
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001328	Specific learning disability
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001355	Megalencephaly
HP:0001387	Joint stiffness
HP:0001476	Delayed closure of the anterior fontanelle
HP:0001612	Weak cry
HP:0002013	Vomiting
HP:0002020	Gastroesophageal reflux
HP:0002033	Poor suck
HP:0002069	Bilateral tonic-clonic seizure
HP:0002179	Opisthotonus
HP:0002200	Pseudobulbar signs
HP:0002360	Sleep disturbance
HP:0002376	Developmental regression
HP:0002421	Poor head control
HP:0002465	Poor speech
HP:0002493	Upper motor neuron dysfunction
HP:0002521	Hypsarrhythmia
HP:0002540	Inability to walk
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0004302	Functional motor deficit
HP:0007256	Abnormal pyramidal sign
HP:0007305	CNS demyelination
HP:0010841	Multifocal epileptiform discharges
HP:0011097	Epileptic spasm
HP:0011342	Mild global developmental delay
HP:0011471	Gastrostomy tube feeding in infancy
HP:0011968	Feeding difficulties
HP:0012379	Abnormal circulating enzyme concentration or activity
HP:0012444	Brain atrophy
HP:0012751	Abnormal basal ganglia MRI signal intensity
HP:0012762	Cerebral white matter atrophy
HP:0025013	Decerebrate rigidity
HP:0025053	Elevated brain N-acetyl aspartate level by MRS
HP:0025405	Visual fixation instability
HP:0032273	Increased circulating N-acetylaspartic acid concentration
HP:0032274	Increased CSF N-acetylaspartic acid concentration
HP:0034649	Elevated urine N-acetylaspartic acid level
HP:0040196	Mild microcephaly
HP:0040288	Nasogastric tube feeding
HP:0200136	Oral-pharyngeal dysphagia

GWAS associations

1 associations:

Study	Trait	p-value
GCST001712_57	Myopia (pathological)	4e-16

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0004207	pathological myopia

MeSH disease descriptors

5 disease descriptors:

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D017825	Canavan Disease	C10.228.140.163.100.362.375; C10.228.140.695.625.375; C10.314.400.375; C10.574.500.300; C16.320.400.150; C16.320.565.189.362.375; C18.452.132.100.362.375; C18.452.648.189.362.375
D003924	Diabetes Mellitus, Type 2	C18.452.394.750.149; C19.246.300
C562683	Cystinosis, Late-Onset Juvenile or Adolescent Nephropathic Type *(supp.)*
C535765	Cystinosis, ocular nonnephropathic *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

33 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	affects expression, decreases methylation, increases expression, increases methylation	4
Benzo(a)pyrene	increases expression, increases methylation, affects methylation	2
Dexamethasone	increases expression, affects cotreatment	2
Nickel	decreases expression	2
Zinc	affects binding	2
Cyclosporine	decreases expression	2
bisphenol F	increases expression	1
alpha phellandrene	increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	affects cotreatment, increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sodium arsenite	affects methylation	1
1,10-phenanthroline	decreases activity	1
CGP 52608	affects binding, increases reaction	1
O,O-diethylphosphorylcholine iodide	decreases activity	1
quinocetone	increases expression	1
bisphenol S	increases expression	1
incobotulinumtoxinA	increases expression	1
Troglitazone	increases expression	1
Acetaminophen	decreases expression	1
Edetic Acid	decreases activity	1
Ethyl Methanesulfonate	increases expression	1
Folic Acid	decreases expression	1
Formaldehyde	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Methyl Methanesulfonate	increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases expression, increases methylation	1

Cellosaurus cell lines

20 cell lines: 10 induced pluripotent stem cell, 7 finite cell line, 3 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0P14	GM00059	Finite cell line	Female
CVCL_0P15	GM00060	Finite cell line	Male
CVCL_0P45	GM04268	Finite cell line	Male
CVCL_0P73	GM17821	Transformed cell line	Female
CVCL_0P74	GM18929	Transformed cell line	Male
CVCL_7415	GM04663	Finite cell line	Female
CVCL_A5RK	CD#59 ipsC	Induced pluripotent stem cell	Female
CVCL_A5RL	CD#60 ipsC	Induced pluripotent stem cell	Male
CVCL_A5RM	CD#68 iPSC	Induced pluripotent stem cell	Male
CVCL_A5RN	FF08711992	Finite cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 301 trials:

NCT	Phase	Status	Title
NCT00006163	Phase 4	COMPLETED	Computer-assisted Diabetes Self-management Interventions
NCT00036504	Phase 4	COMPLETED	Efficacy and Safety of Twice-Daily Insulin Lispro Low Mixture Compared to a Once-Daily Long Acting Insulin Comparator in Patients Who Have Been Using One or More Oral Antihyperglycemic Agents Without Insulin
NCT00044460	Phase 4	COMPLETED	Efficacy and Safety In Poorly Controlled Type 2 Diabetics
NCT00095446	Phase 4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	Phase 4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00110370	Phase 4	COMPLETED	Comparing Pre-Mixed Insulin With Insulin Glargine Combined With Rapid-Acting Insulin in Patients With Type 2 Diabetes
NCT00110448	Phase 4	COMPLETED	Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial
NCT00118950	Phase 4	COMPLETED	Effect of Metformin Versus Repaglinide Treatment in Non-Obese Type 2 Diabetic Patients Uncontrolled by Diet
NCT00118963	Phase 4	COMPLETED	Effect of Repaglinide Versus Metformin Treatment in Non-Obese Patients With Type-2-Diabetes
NCT00121966	Phase 4	COMPLETED	South Danish Diabetes Study: Evaluation of the Antidiabetic Treatment of Type 2 Diabetes Mellitus
NCT00123604	Phase 4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00123643	Phase 4	COMPLETED	Vascular Effects of Rosiglitazone Versus Glyburide in Type 2 Diabetic Patients
NCT00124397	Phase 4	COMPLETED	Atorvastatin and Endothelial Function in Type 2 Diabetes Mellitus (ATTEND-Study)
NCT00129233	Phase 4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00133718	Phase 4	COMPLETED	A 2 Year Trial of Patients With Type 2 Diabetes Focusing on Cardiovascular Diagnostics and Metabolic Control
NCT00135070	Phase 4	TERMINATED	Hospital In-Patient Insulin Study
NCT00141232	Phase 4	COMPLETED	Evaluating Atorvastatin With Omega-3 Fatty Acids in Cardiovascular Risk Reduction in Patients With Type 2 Diabetes
NCT00144144	Phase 4	UNKNOWN	A Study on Ca Blocker Versus AII Antagonists in Hypertension With Type 2 Diabetes
NCT00149331	Phase 4	COMPLETED	The Effects of Two Education Strategies About Insulin on Patient Preferences and Perceptions About Insulin Therapy
NCT00162357	Phase 4	COMPLETED	Post-PCI:Cardiac Imaging in Patients With Diabetes to Detect Coronary Artery Blockages Previously Opened by Angioplasty
NCT00174681	Phase 4	COMPLETED	Tulip Study: Testing the Usefulness of Lantus When Initiated Prematurely In Patients With Type 2 Diabetes
NCT00174824	Phase 4	COMPLETED	Comparison of Insulin Glargine and NPH Human Insulin in Progression of Diabetic Retinopathy in Type 2 Diabetic Patients
NCT00177398	Phase 4	COMPLETED	Effect of Glargine Insulin on Glucose Control in Hospitalized Patients Who Receive Tube Feedings
NCT00179400	Phase 4	COMPLETED	The Role of Acute Combined PPAR Alpha and Gamma Stimulation on Insulin Action in Humans
NCT00184561	Phase 4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	Phase 4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00191178	Phase 4	COMPLETED	Effects of Insulin in Perceived Mood Symptoms in Patients With Type 2 Diabetes
NCT00191282	Phase 4	COMPLETED	Hyperglycemia and Cardiovascular Outcomes With Type 2 Diabetes
NCT00191464	Phase 4	COMPLETED	Long-Term Effects of Insulin Plus Metformin Regimens on the Overall and Postprandial Glycemic Control of Patients With Type 2 Diabetes
NCT00192803	Phase 4	UNKNOWN	Non-Insulin Dependent Diabetes Mellitus (NIDDM) and Angiotensin Converting Enzyme 2 (ACE2): Diabetic Patients Treated With Antihypertensive Drugs
NCT00202033	Phase 4	COMPLETED	Impact of Self-Monitoring Blood Glucose Frequency on Glycemic Control in Patients With Type 2 Diabetes
NCT00205660	Phase 4	COMPLETED	Changes in Adiposity, Metabolic Measures From Atypicals to Aripiprazole
NCT00212290	Phase 4	COMPLETED	Insulin Resistance and Central Nervous System (CNS) Function in Type 2 Diabetes
NCT00212303	Phase 4	COMPLETED	Exercise Training in Type 2 Diabetes and Hypertension
NCT00225342	Phase 4	WITHDRAWN	Study Protocol for Rosiglitazone Versus Gliclazide in Diabetics With Angina
NCT00238472	Phase 4	COMPLETED	A Pilot Study to Evaluate the Effects of Nateglinide vs. Glibenclamide on Renal Hemodynamics and Albumin Excretion
NCT00239538	Phase 4	COMPLETED	SMOOTH - Blood Pressure Control in Diabetic/Obese Patients
NCT00240253	Phase 4	COMPLETED	A Study Evaluating the Efficacy and Safety of Adding Symlin® to Lantus® (Insulin Glargine) in Subjects With Type 2 Diabetes
NCT00240422	Phase 4	COMPLETED	Trial to Compare the Effects of Either Telmisartan (40-80 mg PO Once Daily) or Ramipril (5-10 mg PO Once Daily) on Renal Endothelial Dysfunction in Hypertensive Patients With Type 2 Diabetes
NCT00241085	Phase 4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus
NCT00241605	Phase 4	COMPLETED	AVANDAMET Versus Metformin For Type 2 Diabetes Mellitus
NCT00254085	Phase 4	UNKNOWN	Substitution of First Phase Insulin Response in Patient With Type 2 Diabetes.
NCT00258804	Phase 4	COMPLETED	Insulin Glargine During and After the Period of Fasting in Ramadan
NCT00262548	Phase 4	COMPLETED	C-Reactive Protein (CRP) in Obese Diabetic Women
NCT00264589	Phase 4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00264901	Phase 4	COMPLETED	Comparison of Self Adjustment Versus Standard of Care Treatment in Subjects With Type 2 Diabetes
NCT00265746	Phase 4	WITHDRAWN	Prevention of Diabetes Mellitus Development in Women Who Had Already Experienced A Gestational Diabetes
NCT00268645	Phase 4	COMPLETED	Insulin Glargine in Type 2 Diabetes
NCT00272077	Phase 4	COMPLETED	Insulin Glargine in Type 2 Diabetes Mellitus
NCT00272831	Phase 4	COMPLETED	The Use of Cilostazol in Patients With Diabetic Nephropathy
NCT00274274	Phase 4	COMPLETED	Efficacy and Safety of a Fixed or a Flexible Supplementary Insulin Therapy in Type 2 Diabetes
NCT00279201	Phase 4	COMPLETED	The DURABLE Trial: Evaluating the Durability of Starter Insulin Regimens in Patients With Type 2 Diabetes (IOOV)
NCT00282360	Phase 4	COMPLETED	Effect of Metabolic Therapy in Patients With Chronic Ischemic Heart Disease
NCT00282451	Phase 4	COMPLETED	Effect of Biphasic Insulin Compared to Biphasic Insulin Combined With Insulin Aspart, With or Without Metformin in Type 2 Diabetes
NCT00283049	Phase 4	TERMINATED	Insulin Glargine Injection Treatment in Place of Thiazolidinedione (TZD), Sulfonylurea, or Metformin in Triple Agent Therapy for Type 2 Diabetes Mellitus (T2DM) Adult Subjects With Unsatisfactory Control
NCT00283777	Phase 4	COMPLETED	Chromium and Insulin Action
NCT00290394	Phase 4	COMPLETED	Ambulatory Blood Pressure Reduction After Rosiglitazone Treatment In Normotensive Type 2 Diabetic Patients
NCT00296296	Phase 4	COMPLETED	Immunosuppression Impact on the Metabolic Control of Kidney Transplant With Pre-Existing Type 2 Diabetes (DM)
NCT00300911	Phase 4	COMPLETED	Effects of Rosiglitazone on Plasma BNP Levels and Left Ventricular Dysfunction
NCT00306176	Phase 4	COMPLETED	Rosiglitazone and Exercise in Patients With Type 2 Diabetes Mellitus