AUH

protein-coding

AU RNA binding methylglutaconyl-CoA hydratase

Gene summary

This gene encodes bifunctional mitochondrial protein that has both RNA-binding and hydratase activities. The encoded protein is a methylglutaconyl-CoA hydratase that catalyzes the hydration of 3-methylglutaconyl-CoA to 3-hydroxy-3-methyl-glutaryl-CoA, a critical step in the leucine degradation pathway. This protein also binds AU-rich elements (AREs) found in the 3' UTRs of rapidly decaying mRNAs including c-fos, c-myc and granulocyte/ macrophage colony stimulating factor. ARE elements are involved in directing RNA to rapid degradation and deadenylation. This protein is localizes to the mitochondrial matrix and the inner mitochondrial membrane and may be involved in mitochondrial protein synthesis. Mutations in this gene are the cause of 3-methylglutaconic aciduria, type I. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

MANE transcript

NM_001698.3

Inheritance

ClinVar variants

P:39U:130B:53

Top phenotype

3-methylglutaconic aciduria, type I

gnomAD constraint

pLI —, LoF o/e 0.58

Max pathogenic AF

—

Genomic locus

chr9:91,213,815-91,361,918

External References & Databases

Ensembl (ENSG00000148090)

Transcript & Mutation Effects

hg38 • Region Span ~148.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

3-methylglutaconic aciduria type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009610

Submitter: Labcorp Genetics (formerly Invitae)

3-methylglutaconic aciduria type 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009610

Submitter: Orphanet

3-methylglutaconic aciduria type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009610

Submitter: ClinGen

AUH was first reported in relation to autosomal recessive 3-methylglutaconic aciduria type 1 in 2002 (IJlst et al., PMID: 12434311). At least 11 unique variants (splicing errors, nonsense, frameshift, and missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in 9 probands in 8 publications (PMIDs: 21840233, 28438368, 20855850, 17130438, 16354225, 15033206, 12655555, 12434311). Variants in this gene segregated with disease in 2 additional family members. This gene-disease association is supported by the biochemical function of AUH as a 3-methylglutaconyl-CoA hydratase and its altered function in non-patient cells (PMID: 16640564). In summary, AUH is definitively associated with autosomal recessive 3-methylglutaconic aciduria type 1.

3-methylglutaconic aciduria type 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009610

Submitter: G2P

3-methylglutaconic aciduria type 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009610

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

3-methylglutaconic aciduria, type IAR

Manifestation: Biochemical; Neurologic; Ophthalmologic

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: Dietary measures (leucine restriction) have been suggested

Refs: 720359; 3082934; 1710267; 1375542; 9762598; 10070612; 12434311; 15033206; 16354225; 17130438; 20855850; 21840233; 23296368

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AUH variants in ClinVar

6 Conditions Cataloged

3-methylglutaconic aciduria type 1Total: 202

not providedTotal: 63

Inborn genetic diseasesTotal: 49

not specifiedTotal: 28

AUH-related disorderTotal: 17

3-Methylglutaconic aciduriaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001698.3. 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			3 clinvar	44 clinvar	1 clinvar	48
missense	2 clinvar	8 clinvar	122 clinvar	6 clinvar	1 clinvar	139
nonsense	1 clinvar	3 clinvar	1 clinvar			5
start loss			1 clinvar			1
frameshift	9 clinvar	5 clinvar				14
splice donor/acceptor (+/-2bp)	4 clinvar	7 clinvar	3 clinvar	1 clinvar		15
Total	16	23	130	51	2	222

Highest pathogenic variant AF is 0.000058236572

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 65 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001698.3	RefSeq	NP_001689.1	10	MANE Select
ENST00000375731.9	Ensembl	ENSP00000364883.5	10	MANE Select
NM_001306190.2	RefSeq	NP_001293119.1	9	Standard
NM_001351431.2	RefSeq	NP_001338360.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
auh	Danio rerio	Structure: leucine metabolic process Quality: disrupted abnormal

Gene / Model

Organism

Observed Phenotype

auh

Danio rerio

Structure: leucine metabolic process

Quality: disrupted

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Valine, leucine and isoleucine degradation - Homo sapiens (human)
3-Methylglutaconic Aciduria Type I
Valine, Leucine and Isoleucine Degradation
2-Methyl-3-Hydroxybutryl CoA Dehydrogenase Deficiency
Isovaleric Aciduria

Biological Process

leucine catabolic process
fatty acid beta-oxidation
branched-chain amino acid catabolic process

Molecular Function

mRNA 3'-UTR binding
enoyl-CoA hydratase activity
methylglutaconyl-CoA hydratase activity
itaconyl-CoA hydratase activity

Cellular Component

mitochondrion
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375731
Coding exons: 10
Length: 148099
Individuals with no LoFs: 125684
Homozygous LoFs: 0
Heterozygous LoFs: 64
Defined: 125748
p: 0.000255

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.342	169	182	0.929	0.00000952	2129
Missense (PolyPhen)		62	83.615	0.7415		927
Synonymous	0.196	67	69.1	0.970	0.00000390	706
Loss of Function	1.68	11	18.9	0.582	0.00000107	217

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.0010	0.0010	notable
European (Non-Finnish)	0.00020	0.00019	rare
South Asian	0.00020	0.00020	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the conversion of 3-methylglutaconyl-CoA to 3- hydroxy-3-methylglutaryl-CoA (PubMed:11738050, PubMed:12434311, PubMed:12655555). Also has itaconyl-CoA hydratase activity by converting itaconyl-CoA into citramalyl-CoA in the C5- dicarboxylate catabolism pathway (PubMed:29056341). The C5- dicarboxylate catabolism pathway is required to detoxify itaconate, a vitamin B12-poisoning metabolite (PubMed:29056341). Has very low enoyl-CoA hydratase activity (PubMed:7892223). Was originally identified as RNA-binding protein that binds in vitro to clustered 5'-AUUUA-3' motifs (PubMed:7892223). {ECO:0000269|PubMed:11738050, ECO:0000269|PubMed:12434311, ECO:0000269|PubMed:12655555, ECO:0000269|PubMed:7892223, ECO:0000303|PubMed:29056341}.;
Disease: DISEASE: 3-methylglutaconic aciduria 1 (MGA1) [MIM:250950]: An inborn error of leucine metabolism. It leads to an autosomal recessive syndrome with variable clinical phenotype, ranging from delayed speech development to severe psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia. MGA1 can be distinguished from other forms of MGA by the pattern of metabolite excretion: 3-methylglutaconic acid levels are higher than those detected in other forms, whereas methylglutaric acid levels are usually only slightly elevated and there is a high level of 3-hydroxyisovaleric acid excretion (not present in other MGA forms). {ECO:0000269|PubMed:12655555}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.333

Intolerance Scores

LoFtool: 0.801
RVIS EVS: -0.38
RVIS percentile EVS: 27.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.770

Gene Damage Prediction

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